Diversity Center

THERAPEUTICS TARGETING TDP-43 TO TREAT ALZHEIMER'S DISEASE AND RELATED DISORDERS - TDP-43 IS A MIXED PROTEINOPAPTHY IN ALZHEIMER’S DISEASE (AD), AD-TDP, BASED ON SUBSTANTIAL EPIDEMIOLOGICAL DATA CORRELATING TDP-43 INCLUSIONS WITH COGNITIVE DECLINE IN AD PATIENTS. TDP-43 ASSOCIATED AD HAS BEEN TERMED AS LIMBIC-PREDOMINANT AGE-RELATED TDP-43 ENCEPHALOPATHY (LATE) AS WELL AS OTHER ACRONYMS, UNDERLYING THE NEWLY-RECOGNIZED IMPORTANCE OF TDP-43 IN AD (AD-TDP). AD IS THE MOST COMMON CAUSE OF MID- TO LATE-LIFE COGNITIVE IMPAIRMENT AND DEMENTIA, AFFLICTING ~30 MILLION PEOPLE WORLDWIDE BASED ON AN EXTENSIVE REVIEW OF CLINICAL AND PATHOLOGICAL STUDIES, TDP-43 PROTEINOPATHY IS ASSOCIATED WITH AN AMNESTIC DEMENTIA SYNDROME THAT OCCURS IN OLDER ADULTS. A STATISTICAL ANALYSIS OF ATTRIBUTABLE RISK SUGGESTS THAT TDP-43 ASSOCIATED AD IS A MAJOR PUBLIC HEALTH ISSUE ACCOUNTING FOR UP TO 20% OF CASES OF CLINICALLY DIAGNOSED AD DEMENTIA. THIS TDP-43 PROTEINOPATHY IS A DISTINCT CLINICAL AND PATHOLOGICAL ENTITY FROM OTHER TDP-43 ASSOCIATED DISEASES THAT MAY ALSO BE TREATABLE WITH A TDP-43 TARGETED THERAPY, SUCH AS AMYOTROPHIC LATERAL SCLEROSIS (ALS) AND CERTAIN FORMS OF FRONTOTEMPORAL LOBAR DEGENERATION (FTLD-TDP). THEREFORE, SUCCESSFUL COMPLETION OF THIS PROJECT HAS THE POTENTIAL TO IDENTIFY TDP-43-BASED THERAPEUTICS FOR THE TREATMENT OF OTHER DISEASES WHERE TDP-43 PLAYS A MAJOR AND CAUSATIVE ROLE. WE HAVE DISCOVERED SMALL MOLECULES THAT BIND TO TDP-43 IN SUCH A WAY AS TO INHIBIT BINDING OF RNA TO TDP-43 AND PREVENT TDP-43 AGGREGATION, WITH ACTIVITY SUGGESTIVE OF A THERAPEUTIC EFFECT IN THREE MODELS: (1) HUMAN WILD-TYPE AND MUTANT TDP-43 EXPRESSED IN DROSOPHILA, (2) INDUCED MOTOR NEURONS (IMNS) FROM C9ORF72 PATIENT-DERIVED IPSCS, AND (3) MICE EXPRESSING HUMAN TDP-43 (THY1 PROMOTOR). EVIDENCE FROM 2-D NMR STUDIES AND COMPUTATIONAL DOCKING ANALYSIS SUGGESTS THAT THESE INHIBITORS ARE BINDING TO RIBONUCLEOTIDE RECOGNITION MOTIF RRM2 WHICH CONTAINS ONE OF THE AMINO ACIDS INVOLVED IN A CRITICAL AND FUNCTIONALLY-RELEVANT SALT BRIDGE WITH RRM1. A RECENT PET IMAGING STUDY DESCRIBES A METABOLIC MARKER TO POTENTIALLY SELECT AD-TDP PATIENTS FOR CLINICAL TRIALS BASED ON RATIOS OF FDG IMAGING IN DIFFERENT REGIONS OF THE BRAIN. IN THIS PROJECT WE SEEK TO DISCOVER, VALIDATE AND DEVELOP NEW SMALL- MOLECULE INHIBITORS OF NUCLEIC ACID BINDING TO TDP-43 AND TDP-43 AGGREGATION INHIBITORS TO TREAT AD-TDP. AIM 1 IS THE OPTIMIZATION OF IN VITRO POTENCY AND DRUG-LIKE PROPERTIES OF NOVEL TDP-43 LIGANDS INCLUDING PENETRATION INTO THE BRAIN AND ACCEPTABLE HALF-LIFE AND SAFETY MEASURES USING A COMPREHENSIVE BATTERY OF PHARMACEUTICAL INDUSTRY-STANDARD ASSAYS AND CRITERIA. AIM 2 INVOLVES TARGET ENGAGEMENT STUDIES USING HTDP-43 TRANSFECTED IN HEK293T CELLS, PATIENT-DERIVED INDUCED MOTOR NEURONS FROM IPSCS, DYNAMIC LIGHT SCATTERING ANALYSIS OF AGGREGATION, AND X-RAY CRYSTALLOGRAPHY OF LIGANDS BOUND INTO TDP-43. AIM 3 IS EVALUATION IN ANIMAL MODELS OF TDP-43 PATHOLOGY, INITIALLY USING A THY1 PROMOTER FOLLOWED BY A HTDP-43 BASED MOUSE MODEL THAT DEMONSTRATES COGNITIVE IMPAIRMENT IN THE ABSENCE OF LOCOMOTOR DEFICITS. AIM 4 INCLUDES IND-ENABLING STUDIES, SCALE-UP SYNTHESIS, MULTI-SPECIES PK AND RODENT TOXICITY.

RILUZOLE PRODRUGS FOR MELANOMA AND ALS

NEW ANTIFUNGAL AGENTS AS TOPICAL AND SYSTEMIC THERAPIES FOR WOUND AND INVASIVE INFECTIONS

DEVELOPMENT OF SMALL ANTIMICROBIAL PEPTIDE MIMICS AS DRUG-RESISTANT AND SUSCEPTIB

TRYPANOCIDAL AGENTS THAT KILL MULTIPLE STAGES OF THE TRYPANOSOMA CRUZI LIFE CYCLE - ABSTRACT. CHAGAS DISEASE IS A NEGLECTED TROPICAL DISEASE AND HAS BEEN DESIGNATED AS A RESEARCH PRIORITY BY NIAID AND AN SBIR RESEARCH TOPIC OF INTEREST. SIX MILLION INDIVIDUALS ARE INFECTED AND 8,000 DEATHS WERE CAUSED BY CHAGAS IN 2015 IN MOSTLY CENTRAL AND SOUTH AMERICA BY ADVANCED FORMS OF THE DISEASE SUCH AS CHAGAS HEMORRHAGIC FEVER. THE COST ASSOCIATED WITH CHAGAS DISEASE TREATMENT GLOBALLY IS ESTIMATED TO BE ~$7 BILLION. CHAGAS DISEASE IS CAUSED BY THE PARASITIC PROTIST TRYPANOSOMA CRUZI (T. CRUZI) AND SPREAD BY TRIATOMINAE, OR "KISSING BUGS". WHILE ENDEMIC IN SOUTH AMERICA, IT IS SPREAD TO PEOPLE LIVING ELSEWHERE DUE TO IMMIGRATION OF INFECTED PATIENTS AND TRAVEL TO ENDEMIC REGIONS. NO VACCINE IS CURRENTLY AVAILABLE AND THE ONLY DRUGS USED TO TREAT CHAGAS, THE NITRO ARYL COMPOUNDS NIFURTIMOX AND BENZNIDAZOLE, LOSE EFFECTIVENESS IN THE CHRONIC PHASE AS THE PARASITE DEVELOPS RESISTANCE, AND THEY CAUSE LIMITING ADVERSE EVENTS AS WELL. NEW MEDICATIONS ACTING VIA NOVEL MECHANISMS ARE URGENTLY NEEDED TO ELIMINATE THE PARASITE IN CHRONIC PATIENTS SUFFERING AND DYING FROM CHAGAS DISEASE. NOVEL COMPOUNDS SYNTHESIZED AT FOX CHASE CHEMICAL DIVERSITY CENTER (FCCDC) HAVE BEEN TESTED AT MULTIPLE COLLABORATOR SITES: GSK TRES CANTOS OPEN LAB FOUNDATION IN TRES CANTOS, SPAIN; NEW YORK UNIVERSITY; UNIVERSITY OF DUNDEE, SCOTLAND; AND THE SWISS TROPICAL PUBLIC HEALTH INSTITUTE, ALL RESEARCH FACILITIES DEDICATED TO CURING NEGLECTED TROPICAL DISEASES. THE ANALOGS TESTED DISPLAYED EXCELLENT ACTIVITY AGAINST THE T. CRUZI PARASITE IN BOTH ITS REPLICATIVE (AMASTIGOTE) AND INFECTIVE (TRYPOMASTIGOTE) FORMS AS FOUND IN PHENOTYPIC SCREENING ASSAYS. THE COMPOUNDS DO NOT ACT THROUGH ANY KNOWN MECHANISM OF ACTION AND DISPLAY LITTLE TO NO TOXICITY TO HOST CELLS, UNLIKE THE STANDARDS OF CARE NIFURTIMOX AND BENZNIDAZOLE. FURTHER, IN VIVO TESTING IN A MURINE MODEL FOR CHAGAS DISEASE (NYU) CONFIRMED POTENT ANTIPARASITIC ACTIVITY. THE LEAD COMPOUNDS ARE PROPRIETARY TO FCCDC AND A PROVISIONAL U.S. PATENT APPLICATION HAS BEEN FILED. THE ACTIVITY SEEN FOR THE SERIES HAS GENERATED GREAT INTEREST AT THE NON-PROFIT DRUGS FOR NEGLECTED DISEASES INITIATIVE (DNDI). DNDI EVALUATES MANY POTENTIAL INTERNATIONAL COLLABORATIONS EACH YEAR BUT ONLY SELECTS THE MOST PROMISING FOR RESOURCE INVESTMENT. FOLLOWING EVALUATION OF OUR PROJECT, DNDI HAS COMMITTED ADDITIONAL T. CRUZI TESTING GRATIS AT BOTH THE UNIVERSITY OF DUNDEE AND THE SWISS TROPICAL AND PUBLIC HEALTH INSTITUTE IN ORDER TO EVALUATE POTENCY AND INVESTIGATE MECHANISM OF ACTION. OUR AIMS TO DEVELOP THIS CHEMOTYPE FROM LEAD COMPOUND TO PRECLINICAL CANDIDATE IS (1) OPTIMIZE THE POTENCY BY EXPLORING THE SAR OF OUR NOVEL LEAD USING ITERATIVE MEDICINAL CHEMISTRY SYNTHESI, (2) CHARACTERIZE THE BIOCHEMICAL PROPERTIES OF THE COMPOUNDS TO OPTIMIZE ANTIPARASITIC ACTIVITY (NYU, DNDI), AND (3) PERFORM IN VIVO TESTS IN ACUTE AND CHRONIC CHAGAS DISEASE MOUSE MODELS (NYU) AS WELL AS EVALUATE AND IMPROVE ADME PROPERTIES OF ADVANCED LEADS AS REQUIRED. THE GOAL OF THIS PROGRAM IS TO COMPLETE MANY OF THE STUDIES NECESSARY FOR FILING AN INVESTIGATIONAL NEW DRUG (IND) APPLICATION FOR NEW AGENTS TO TREAT CHAGAS DISEASE AS MONOTHERAPY OR IN COMBINATION WITH EXISTING AGENTS.

OPTIMIZING A STAPLED-PEPTIDE THAT SPECIFICALLY TARGETS HSV-1 TO TREAT HERPES OCULAR KERATITIS - ABSTRACT INFECTION OF THE EYE BY HERPES SIMPLEX VIRUS-1 (HSV-1) CAN RESULT IN HERPES KERATITIS (HK), WHICH IS THE LEADING CAUSE OF INFECTIOUS CORNEAL BLINDNESS WORLDWIDE. IN THE U.S., NEARLY 500,000 INDIVIDUALS EXPERIENCE OCULAR HERPES INFECTIONS THAT ARE OFTEN RECURRENT AND CULMINATE IN PROGRESSIVE CORNEAL SCARRING AND LOSS OF VISION. THE GOLD STANDARD TREATMENT IS ACYCLOVIR (ACV) THAT TARGETS HSV-1 THYMIDINE KINASE (TK). HOWEVER, EMERGENCE OF ACV VIRAL RESISTANT MUTANTS IN 7-14% OF OCULAR HK PATIENTS HAS CREATED THE URGENT NEED TO DISCOVER A SECOND DRUG DIRECTED AGAINST A DIFFERENT HSV-1 TARGET. A NEW CLASS OF ANTIVIRAL TARGETS ARE PROCESSIVITY FACTORS (PFS) THAT ARE ESSENTIAL FOR TETHERING THEIR COGNATE POLYMERASES (POLS) TO THE TEMPLATE TO ENABLE CONTINUOUS DNA SYNTHESIS. DURING HSV-1 REPLICATION, THE DNA-ANCHORED PF BINDS TO THE EXTREME C-TERMINUS OF POL (C-POL) TO KEEP POL FROM DISSOCIATING FROM THE VIRAL TEMPLATE. WHEN CO-CRYSTALLIZED WITH ITS PF, THE C-TERMINUS OF THE VIRAL POL (C-POL) FORMS AN A-HELIX, WITH ONE FACE MAKING MULTIPLE BONDS WITH SEVERAL RESIDUES OF PF WHILE THE OTHER FACE IS SOLVENT EXPOSED. OUR GOAL IS TO DEVELOP A NOVEL ANTIVIRAL DRUG THAT SPECIFICALLY TARGETS HERPES PF FOR THE PURPOSE OF TREATING ACV RESISTANT HK. STAPLED A-HELICAL PEPTIDES HAVE EMERGED FOR USE IN TARGETING PROTEIN-PROTEIN INTERACTIONS THAT OFTEN DISPLAY AS LONG FLAT SURFACES WHICH ARE DIFFICULT FOR SMALL MOLECULES TO BIND EFFICIENTLY. PEPTIDE A-HELICES ARE IDEAL STRUCTURAL MOTIFS FOR INCORPORATING CHEMICAL STAPLES TO PROVIDE RIGIDITY TO MAKE NATURAL BONDS WITH RESIDUES ON THE TARGET PROTEIN. MOREOVER, STAPLES CAN CREATE A PROTEASE SHIELD TO PROLONG RESIDENCE TIME. WE HAVE NOW ENGINEERED A STAPLED PEPTIDE OF C-POL (SPEP7B) THAT BLOCKS THE MECHANISM OF PROCESSIVE DNA SYNTHESIS IN VITRO AND HSV-1 INFECTION IN HUMAN ORGANOTYPIC (3D) CORNEAL EPITHELIAL CELLS; THE UNSTAPLED PEPTIDE IS NON-INHIBITORY. SPEP7B WAS SHOWN TO ELIMINATE HSV-1 VIRAL DNA IN INFECTED CELLS WHILE FAILING TO BLOCK A DIFFERENT VIRUS. IMPORTANTLY, SPEP7B EXHIBITS UNDETECTABLE TOXICITY (CC50>100ΜM) BY TWO DIFFERENT ASSAYS IN HUMAN OCULAR EPITHELIAL CELLS. OUR GOAL IS TO ENTER SPEP7B INTO PRECLINICAL DEVELOPMENT AS A TOPICAL TO TREAT HK. THIS WILL BE ACCOMPLISHED BY CONDUCTING A SERIES OF AIMS THAT INCLUDE SCALEUP OF SPEP7B AND EVALUATING TWO FORMULATIONS FOR DELIVERY OF SPEP7B INTO HUMAN 3D CULTURES AND THEN EX-VIVO EXCISED RABBIT CORNEA FOR PERMEABILITY AND TOXICITY. THESE STUDIES ARE ESSENTIAL TO CONFRONT THE PHYSIOLOGICAL AND ANATOMICAL BARRIERS TO TOPICAL OCULAR DELIVERY. IN VIVO STUDIES WILL EVALUATE SPEP7B FOR TOLERABILITY, GENOTOXICITY, PK, AND REPEAT DOSING. AN EFFICACY STUDY WILL EVALUATE SPEP7B FOR CLINICAL CURE AND VIRAL CLEARING. BACKUP ANALOGS OF SPEP7B WILL BE PREPARED AND EVALUATED FOR RISK MITIGATION. A MODEL FOR NEW ANTIVIRAL DRUGS: CLOSELY ALIGNED WITH THIS APPROACH IS THE POTENTIAL FOR USING PFS AND STAPLED PEPTIDES OF OTHER VIRUSES FOR TREATING UNMET MEDICAL NEEDS CAUSED BY INFECTIONS THAT LEAD TO DELETERIOUS COMPLICATIONS.

DEVELOPMENT OF SMALL MOLECULE THERAPEUTICS TARGETING HEMORRHAGIC FEVER VIRUSES - SUMMARY: THE ULTIMATE GOAL OF THIS PHASE II APPLICATION IS TO DEVELOP NOVEL SMALL MOLECULE, BROAD-SPECTRUM THERAPEUTICS AGAINST VIRAL INFECTIONS CAUSED BY FILOVIRUSES, ARENAVIRUSES, AND OTHER VIRUSES THAT DEPEND ON THE PPXY L-DOMAIN MOTIF FOR EGRESS AND SPREAD OF INFECTION. SOME OF THESE VIRUSES, INCLUDING EBOLA (EBOV), MARBURG (MARV), AND LASSA FEVER (LAFV) VIRUSES, ARE HIGHLY PATHOGENIC AND CLASSIFIED AS CATEGORY A BIOTERROR PATHOGENS. WE AND OTHERS HAVE DETERMINED THAT EFFICIENT BUDDING OF THESE EMERGING HUMAN PATHOGENS DEPENDS ON THE SUBVERSION OF HOST PROTEINS, SUCH AS NEURAL PRECURSOR CELL EXPRESSED DEVELOPMENTALLY DOWN-REGULATED PROTEIN 4 (NEDD4), BY PPXY L-DOMAINS IN THE MATRIX PROTEINS OF THESE RNA VIRUSES. THE IDENTIFICATION AND DEVELOPMENT OF SMALL MOLECULE INHIBITORS THAT INTERFERE WITH THESE VIRUS-HOST INTERACTIONS SHOULD EFFECTIVELY BLOCK VIRUS EGRESS, DISEASE PROGRESSION, AND TRANSMISSION. IN THESE EFFORTS WE HAVE DISCOVERED SEVERAL CHEMICAL SERIES OF SMALL MOLECULE INHIBITORS OF THE HOST NEDD4/VIRUS PPXY COMPLEX IMPORTANT FOR VIRAL EGRESS WHICH LED TO ONE ANALOG POSSESSING PROOF OF CONCEPT IN VIVO ACTIVITY IN A MARBURG VIRUS CHALLENGED MOUSE MODEL. AS FDA APPROVED THERAPEUTIC AGENTS FOR THE TREATMENT OF THESE MOST OF THESE VIRAL INFECTIONS ARE NOT AVAILABLE, OUR IDENTIFICATION OF VIRUS-HOST INHIBITORS THAT MAY PREVENT VIRUS SPREAD WILL FILL A SIGNIFICANT UNMET NEED. MOREOVER, THESE INHIBITORS WILL BE BROAD-SPECTRUM, AND THEREFORE WILL LIKELY BE EFFECTIVE AGAINST NEWLY EMERGING VIRUSES AS WELL AS VIRAL VARIANTS. AS DESCRIBED BELOW, WE WILL USE A RIGOROUS MULTIFACETED APPROACH TO IDENTIFY, DEVELOP, AND VALIDATE PPXY BUDDING INHIBITORS IDENTIFIED IN PHASE I AS POTENT, BROAD-SPECTRUM ANTIVIRALS. THE GOAL OF THIS PHASE II STTR GRANT APPLICATION IS TO OPTIMIZE OUR LEAD INHIBITORS OF VP40 PPXY-NEDD4 INTERACTIONS TO GENERATE FULL- FLEDGED PREDEVELOPMENT DRUG CANDIDATES READY FOR IND DIRECTED STUDIES. THIS WILL BE ACCOMPLISHED BY COMBINING THE PHARMACEUTICAL AND MEDICINAL CHEMISTRY EXPERTISE OF THE SCIENTISTS AT THE FOX CHASE CHEMICAL DIVERSITY CENTER, INC. (FCCDC) WITH THE EXPERTISE AND EXPERIENCE IN THE EXPERIMENTAL ASPECTS OF ANTIVIRAL THERAPY OF THE HARTY LAB AT THE UNIVERSITY OF PENNSYLVANIA. WE WILL REALIZE THIS GOAL BY OPTIMIZING OUR EXISTING SERIES OF INHIBITORS, EXEMPLIFIED BY IN VIVO ACTIVE FC-10696, FOR IMPROVED POTENCY AND ORAL DRUG PROPERTIES (AIM 1), EVALUATING NEW COMPOUNDS BASED ON TWO POTENT SERIES FOR THEIR ABILITY TO SPECIFICALLY INHIBIT PPXY-NEDD4 INTERACTIONS AND SUBSEQUENT VLP AND SURROGATE VIRUS EGRESS (AIM 2), IDENTIFYING COMPOUNDS HAVING SUITABLE DRUG PROPERTIES AND SELECTIVITY USING IN VITRO AND IN VIVO ADMET EVALUATION (AIM 3), AND EVALUATING COMPOUNDS FOR THEIR ANTIVIRAL EFFICACY AGAINST AUTHENTIC BSL-4 VIRUSES IN VITRO AND IN VIVO (AIM 4).

DEVELOPMENT OF TOPICAL ANTIVIRAL AGENTS FOR TREATING MOLLUSCUM CONTAGIOSUM

DEVELOPMENT OF A PEPTIDE-DRUG CONJUGATE FOR TOPICALLY TREATING THE VIRAL SKIN DISEASE MOLLUSCUM CONTAGIOSUM - ABSTRACT MOLLUSCUM CONTAGIOSUM (MC) IS A HIGHLY CONTAGIOUS SKIN DISEASE CAUSED BY THE POXVIRUS, MCV. IT REMAINS AN UNMET MEDICAL NEED DUE TO LACK OF AN APPROVED ANTIVIRAL DRUG. MC APPEARS AS LESIONS ON THE BODY AND FACE THAT CAN SPREAD AND LAST MONTHS-YEARS BEFORE RESOLVING. LESIONS OCCUR MOST FREQUENTLY IN CHILDREN (5%) AND IMMUNE COMPROMISED INDIVIDUALS (5-18%). THE INFECTION IS CONFINED TO THE EPIDERMAL SKIN LAYERS; IT IS NOT SYSTEMIC. TRANSMISSION SPREADS DIRECTLY FROM PERSON-PERSON CONTACT, AUTOINOCULATION, OR INDIRECT CONTACT WITH FOMITES. A PRINCIPAL CONCERN IS INFECTION OF THE EYELIDS BY RUBBING SKIN LESIONS FROM DISTAL SITES. INFECTION OF THE EYELIDS IS ESPECIALLY DISTRESSFUL AND CAN LEAD TO INFLAMMATION OF THE CONJUNCTIVA CAUSING “PINK EYE” AND FOLLICULAR CONJUNCTIVITIS. CURRENT TREATMENTS CAN BE PAINFUL, CAUSE SCARRING, AND PSYCHOLOGICAL DISTRESS. NONE OF THE CURRENT TREATMENTS THAT INCLUDE A RANGE OF PHYSICAL, CHEMICAL, AND MEDICINAL INTERVENTIONS ARE UNIFORMLY ACCEPTED OR FDA APPROVED. NO MC APPROVED DRUG HAS BEEN DEVELOPED BECAUSE THE VIRUS CANNOT BE GROWN IN TISSUE CULTURE FOR TESTING. WE HAVE NOW MADE 4 MAJOR BREAKTHROUGHS: FIRST, WE IDENTIFIED A PROTEIN TARGET (MD4) OF MCV THAT IS SPECIFIC FOR VIRAL REPLICATION. SECOND, WE CONSTRUCTED A SURROGATE VIRUS (MD4-VV), PROVIDING THE FIRST CELL-BASED SYSTEM FOR SCREENING COMPOUNDS AGAINST THE VIRAL TARGET PROTEIN (MD4) IN INFECTED CELLS. THIRD, WE SYNTHESIZED A SMALL MOLECULE (7269) THAT BINDS A PRECISE REGION OF THE MD4 TARGET PROTEIN TO CAUSE UNFOLDING AND LOSS OF FUNCTION. HOWEVER, ALTHOUGH 7269 BLOCKS INFECTION OF THE SURROGATE VIRUS, WE WERE UNABLE TO IMPROVE ITS POTENCY OR ELIMINATE ITS SLIGHT TOXICITY DESPITE AN INTENSE MEDICINAL CHEMISTRY CAMPAIGN. FOURTH, WE OVERCAME THIS IMPASSE BY CONJUGATING A PEPTIDE TO PRODUCE TRIVALINE-7269 THAT INCREASES ANTIVIRAL POTENCY 6.3-FOLD GREATER THAN THAT OF UNCONJUGATED 7269 WITH NO MEASURABLE TOXICITY. SINCE THE INCREASED POTENCY OF TRIVALINE-7269 IS NOT RELATED TO AN INCREASE IN TARGET BINDING, IT IS LIKELY DUE TO CELL UPTAKE OR STABILITY. THE CHALLENGE FOR FUTURE CLINICAL DRUG DEVELOPMENT IS THAT TRIVALINE-7269 HAS NO RELATED CONJUGATED PEPTIDE ANALOGS OF EQUAL OR GREATER POTENCY TO MITIGATE RISK. TO ADDRESS THIS REQUIREMENT, WE HAVE SYNTHESIZED 68 NEW ANALOGS RELATED TO TRIVALINE-7269 (C-PEP1) FROM WHICH EMERGED C-PEP2 & C-PEP3 EXHIBITING EVEN GREATER ANTIVIRAL POTENCY. OUR GOAL IS TO OPTIMIZE THE 3 C-PEPS TO GENERATE A PRE-CLINICAL LEAD WITH THE OTHER TWO AS BACKUPS TO TOPICALLY TREAT MC LESIONS ON ALL AREAS OF THE SKIN INCLUDING THE EYELIDS. OUR AIMS ARE TO: (I) USE MEDICINAL CHEMISTRY TO GENERATE 100 NEW ANALOGS OF THE C-PEPS; (II) SCREEN THE CHEMICALLY MODIFIED C-PEPS FOR: VALIDATION OF MD4-TARGET ENGAGEMENT, ANTIVIRAL POTENCY, CYTOTOXICITY, BINDING THE MD4 TARGET; (III) USE 3D ORGANOTYPIC SKIN CULTURES AND LIPOSOMES FOR DEVELOPING AND DELIVERING ADVANCED C-PEPS TO TREAT ALL LESIONS, INCLUDING EYELIDS; (IV) ASSAY IN VITRO ADME AND MULTIPLE OFF-TARGET ACTIVITIES; (V) INITIATE PRE-CLINICAL DEVELOPMENT FOR NON-GMP API SCALE-UP AND PRE- FORMULATION MANUFACTURING AND STABILITY.

SMALL MOLECULE ANTAGONISTS OF PF4 FOR THE TREATMENT AND PREVENTION OF HIT

DEVELOPMENT OF SMALL MOLECULE THERAPEUTICS AGAINST SMALLPOX AND OTHER POXVIRUSES

SMALL MOLECULE INHIBITORS OF HIV1 NEF VIRULENCE FACTOR FOR TREATMENT OF HIV_AIDS

SMALL MOLECULE ANTAGONISTS OF PF4 FOR THE TREATMENT AND PREVENTION OF HIT

A NOVEL THERAPEUTIC FOR INVASIVE CANDIDIASIS

PET IMAGING AGENTS FOR THE IN VIVO DETECTION OF TDP-43

AI-DRIVEN DISCOVERY OF IN VIVO CHEMICAL PROBES FOR UNDERSTUDIED TARGETS FOR THE TREATMENT OF ALZHEIMER'S DISEASE AND RELATED DISORDERS (ADRD) - ALZHEIMER’S DISEASE AND RELATED DEMENTIAS (ADRD) ARE DEBILITATING DISEASES THAT ARE INCREASING IN PREVALENCE BEING THE MOST COMMON FORM OF DEMENTIA WORLDWIDE. CURRENT THERAPIES ARE PRIMARILY PALLIATIVE IN NATURE EXCEPT FOR THE RECENT AMYLOID ANTIBODIES WHICH SHOW VARIABLE AND INCREMENTAL EFFICACY IN SLOWING DISEASE PROGRESSION. WE HERE APPLY THE EMERGING TOOLS OF ARTIFICIAL INTELLIGENCE (AI) AND MACHINE LEARNING (ML) TO AID IN THE DISCOVERY OF IN VIVO CHEMICAL PROBES FOR UNDERSTUDIED TARGETS IN AD RESEARCH. THE PROJECT IS CLOSELY ALIGNED WITH THE NIA- FUNDED AD INITIATIVES ACCELERATING MEDICINES PARTNERSHIP IN ALZHEIMER’S DISEASE TARGET DISCOVERY AND PRECLINICAL VALIDATION PROJECT AND THE EMORY-SAGE-SGC-JAX TARGET ENABLEMENT TO ACCELERATE THERAPY DEVELOPMENT FOR AD (TREAT-AD) CENTER. WE WILL EXAMINE ALL 900 PROTEINS CURRENTLY LISTED ON THE TREAT-AD WEBSITE, EVALUATE 15 PER YEAR USING VIRTUAL SCREENING FROM OUR COMPOUND LIBRARIES, AND ADVANCE FIVE OF THESE THROUGH A SERIES OF SAR DEVELOPMENT ACTIVITIES LEADING TO IN VIVO CHEMICAL PROBES WHICH ARE MADE PUBLICLY AVAILABLE THROUGH TREAT-AD AND SHARED WITH THE SCIENTIFIC COMMUNITY. WE WILL LEVERAGE VALIDATED VIRTUAL SCREENING WORKFLOWS FOR NOVEL TARGET DISCOVERY, A PROCESS FOR WHICH WE HAVE EXTENSIVE EXPERIENCE. AIM 1 IS TARGET SELECTION CLOSELY ALIGNED WITH TREAT-AD. AIM 2 IS VIRTUAL SCREENING FOR NOVEL COMPOUNDS WITH DESIRED TARGET BINDING ACTIVITY. AIM 3 IS ASSAY DEVELOPMENT AND TESTING OF TOP HITS FROM AIM 2 PLUS STRUCTURAL ANALOGS. AN AD HOC TARGET PROJECT TEAM WILL BE CREATED FOR EACH TARGET THAT EMERGES FROM AIM 2. AIM 4 INCORPORATES NOVEL AI-DRIVEN ALGORITHM DEVELOPMENT AND TRAINING FOR OPTIMIZING SELECTIVE LEADS FROM AIM 3 HITS. AIM 5 IS MEDICINAL CHEMISTRY REFINEMENT OF THE AI/ML OUTPUTS AND BIOCHEMICAL AND FUNCTIONAL CHARACTERIZATION OF CHMICAL HITS INCLUDING ADME CHARACTERIZATION SUITABLE FOR THE IDENTIFICATION OF PROBES FOR IN VIVO STUDIES. A HIT REVIEW STEERING COMMITTEE (HRSC) WILL REVIEW THE HITS AND LEADS THAT ARE DISCOVERED DURING THE COURSE OF THIS PROJECT TO PROVIDE GUIDANCE AS TO DESIGN AND INTERPRETATION OF STUDIES AS WELL AS WHICH HITS AND CHEMOTYPES TO ADVANCE FURTHER. FINALLY, AIM 6 IS PUBLIC DISSEMINATION OF THE STRUCTURES AND ACTIVITIES OF NEW IN VIVO CHEMICAL PROBES FOR UNDERSTUDIED TARGETS IN AD RESEARCH. SMALL MOLECULE CHEMICAL PROBES ARE VALIDATED FOR FURTHER PROOF OF CONCEPT RESEARCH IF THEY HAVE BINDING OR FUNCTIONAL ACTIVITY AT TARGETS OF INTEREST TO THE EXTENT OF ≤100 NM (PREFERRED) AND IN VIVO PK IN MICE WITH A T1/2 OF ≥60 MINS (PREFERRED), %F (ORAL BIOAVAILABILITY) OF ≥20% AND A BRAIN:PLASMA RATIO OF ≥0.5. IN SUMMARY, 15 TARGETS PER YEAR WILL GO INTO A FULL VIRTUAL SCREEN. BASED ON THE DATA, FIVE TARGETS PER YEAR WILL GO TO EXPERIMENTAL VALIDATION AND SAR DEVELOPMENT. ALL OF THE DATA WILL BE RELEASED ON THE TREAT-AD WEBSITE SO OTHERS CAN PURSUE THE 10 TARGETS PER YEAR THAT WERE NOT FOLLOWED UP ON. WE WILL USE MODERN METHODS IN COMPUTATIONAL CHEMISTRY INCLUDING AI AND ML TO DISCOVER AND CHARACTERIZE NEW IN VIVO CHEMICAL PROBES FOR UNDERSTUDIED TARGETS IN AD RESEARCH. IT IS ANTICIPATED THAT THESE IN VIVO CHEMICAL PROBES WILL BE WIDELY USED BY RESEARCHERS IN THE AD SCIENTIFIC COMMUNITY TO UNDERSTAND THE FUNCTION OF PROMISING NEW TARGETS.

THE LEGAL ASSISTANCE FOR VICTIMS (LAV) GRANT PROGRAM, AUTHORIZED BY 34 U.S.C. 20121, IS INTENDED TO INCREASE THE AVAILABILITY OF CIVIL AND CRIMINAL LEGAL ASSISTANCE NEEDED TO EFFECTIVELY AID VICTIMS (AGES 11 AND OLDER) OF DOMESTIC VIOLENCE, DATING VIOLENCE, SEXUAL ASSAULT, AND STALKING BY PROVIDING FUNDS FOR COMPREHENSIVE DIRECT LEGAL SERVICES TO VICTIMS IN LEGAL MATTERS RELATING TO OR ARISING OUT OF THAT ABUSE OR VIOLENCE. LEGAL ASSISTANCE INCLUDES ASSISTANCE TO VICTIMS OF DOMESTIC VIOLENCE, DATING VIOLENCE, SEXUAL ASSAULT, AND STALKING IN: A) FAMILY, TRIBAL, TERRITORIAL, IMMIGRATION, EMPLOYMENT, ADMINISTRATIVE AGENCY, HOUSING MATTERS, CAMPUS ADMINISTRATIVE, OR PROTECTION OR STAY AWAY ORDER PROCEEDINGS, AND OTHER SIMILAR MATTERS; B) CRIMINAL JUSTICE INVESTIGATIONS, PROSECUTIONS, AND POST-TRIAL MATTERS (INCLUDING SENTENCING, PAROLE, AND PROBATION) THAT IMPACT THE VICTIMS SAFETY AND PRIVACY; C) ALTERNATIVE DISPUTE RESOLUTION, RESTORATIVE PRACTICES, OR OTHER PROCESSES INTENDED TO PROMOTE VICTIM SAFETY, PRIVACY, AND AUTONOMY; AND D) POST-CONVICTION RELIEF PROCEEDINGS IN STATE, LOCAL, TRIBAL, OR TERRITORIAL COURT WHERE THE CONVICTION OF A VICTIM IS RELATED TO OR ARISING FROM DOMESTIC VIOLENCE, DATING VIOLENCE, SEXUAL ASSAULT, STALKING, OR SEX TRAFFICKING. 34 U.S.C. 12291(A)(24)(C) AND (D). THROUGH THIS NEW LEGAL ASSISTANCE FOR VICTIMS PROJECT, THE JUSTICE & DIVERSITY CENTER OF THE BAR ASSOCIATION OF SAN FRANCISCO, IN PARTNERSHIP WITH WOMEN ORGANIZED TO MAKE ABUSE XISTENT (WOMAN, INC.), WILL PROVIDE A HOLISTIC, COORDINATED, AND INTEGRATED SYSTEM OF LEGAL SERVICES FOR LOW-INCOME SURVIVORS OF DOMESTIC VIOLENCE. PLANNED LEGAL SERVICES INCLUDE PROTECTION ORDERS AND FAMILY LAW MATTERS. THE PROJECT WILL ADDRESS THE FOLLOWING PRIORITY AREA: ADVANCE EQUITY AND TRIBAL SOVEREIGNTY BY SPECIFICALLY BENEFITTING THE TARGET POPULATION OF LOW-INCOME MONOLINGUAL SPANISH-SPEAKING LATINX SURVIVORS OF DOMESTIC VIOLENCE RESIDING IN THE CITY AND COUNTY OF SAN FRANCISCO.

DEVELOPMENT OF A PEPTIDE-DRUG CONJUGATE FOR TOPICALLY TREATING THE VIRAL SKIN DISEASE MOLLUSCUM CONTAGIOSUM - ABSTRACT MOLLUSCUM CONTAGIOSUM (MC) IS A HIGHLY CONTAGIOUS SKIN DISEASE CAUSED BY THE POXVIRUS, MCV. IT REMAINS AN UNMET MEDICAL NEED DUE TO LACK OF AN APPROVED ANTIVIRAL DRUG. MC APPEARS AS LESIONS ON THE BODY AND FACE THAT CAN LAST MONTHS-YEARS BEFORE RESOLVING. LESIONS OCCUR MOST FREQUENTLY IN CHILDREN (5%) AND IMMUNE COMPROMISED INDIVIDUALS (5-18%). THE INFECTION IS CONFINED TO THE EPIDERMAL SKIN LAYERS; IT IS NOT SYSTEMIC. TRANSMISSION SPREADS DIRECTLY FROM PERSON-PERSON CONTACT, AUTOINOCULATION OR INDIRECT CONTACT WITH FOMITES. CURRENT TREATMENTS CAN BE PAINFUL, CAUSE SCARRING, AND PSYCHOLOGICAL DISTRESS. NONE OF THE CURRENT TREATMENTS THAT INCLUDE A RANGE OF PHYSICAL, CHEMICAL AND MEDICINAL INTERVENTIONS ARE UNIFORMLY ACCEPTED OR FDA APPROVED. THE REASON WHY NO APPROVED DRUG AGAINST MCV HAS BEEN DEVELOPED IS BECAUSE THE VIRUS CANNOT BE GROWN IN TISSUE CULTURE FOR TESTING. WE HAVE NOW MADE FOUR MAJOR BREAKTHROUGHS: FIRST, WE HAVE IDENTIFIED A PROTEIN TARGET (MD4) OF MCV THAT IS ESSENTIAL FOR REPLICATION. THE MD4 PROTEIN FUNCTIONS AS A PROCESSIVITY FACTOR (PF) THAT TETHERS THE VIRAL POLYMERASE (POL) TO THE TEMPLATE TO ENABLE CONTINUOUS SYNTHESIS OF DNA. SECOND, WE HAVE CONSTRUCTED A MD4- SURROGATE VIRUS (MD4-VV), PROVIDING THE FIRST CELL-BASED SYSTEM FOR SCREENING COMPOUNDS AGAINST AN ESSENTIAL MCV TARGET PROTEIN (MD4) IN INFECTED CELLS. THIRD, WE HAVE SYNTHESIZED A SMALL MOLECULE (7269) THAT THAT BINDS A PRECISE REGION OF THE MD4 TARGET PROTEIN, CAUSING IT TO UNFOLD AND NO LONGER FUNCTION. WHILE 7269 CAN BLOCK INFECTION BY THE SURROGATE VIRUS, WE WERE UNABLE TO IMPROVE ITS POTENCY OR ELIMINATE ITS SLIGHT TOXICITY DESPITE AN INTENSE MEDICINAL CHEMISTRY CAMPAIGN. FOURTH, WE OVERCAME THIS IMPASSE BY CONJUGATING A PEPTIDE TO PRODUCE TRIVALINE-7269 THAT BINDS THE MD4 WITH A POTENCY THAT IS 6.3-FOLD GREATER THAN THAT OF UNCONJUGATED 7269 AND HAS NO MEASURABLE TOXICITY. SINCE TRIVALINE-7269 DOES NOT ALTER DIRECT BINDING TO THE MD4 TARGET, ITS INCREASED POTENCY IS DUE TO CELLULAR PENETRATION AND/OR STABILITY. THE CHALLENGE THAT IMPEDES FURTHER DRUG DEVELOPMENT IS THAT TRIVALINE-7269 HAS NO RELATED ANALOG OF EQUAL OR GREATER POTENCY TO MITIGATE RISK IN THE NEXT STAGES OF DRUG DEVELOPMENT. THE GOAL IS TO IDENTIFY ANALOGS OF TRIVALINE-7269 OF EQUAL OR GREATER POTENCY AS ESSENTIAL BACKUPS. AIM 1 WILL UTILIZE MEDICINAL CHEMISTRY TO SYNTHESIZE ANALOGS OF TRIVALINE-7269. THE FOCUS WILL BE TO VARY BOTH THE PEPTIDE AND LINKER PORTIONS OF TRIVALINE-7269. THE 7269 PORTION WILL NOT BE MODIFIED SINCE IT HAS ALREADY BEEN OPTIMIZED. WE WILL PRODUCE 30-40 ANALOGS. AIM 2 WILL EVALUATE NEW ANALOGS FOR ANTIVIRAL POTENCY AGAINST THE SURROGATE VIRUS; CYTOTOXICITY; BLOCKING IN VITRO PROCESSIVE DNA SYNTHESIS; BINDING TO THE MD4 TARGET. AIM 3 WILL EVALUATE STRUCTURALLY DISTINCT ANALOGS FOR IN VITRO ADME ACTIVITIES THAT ARE RELEVANT FOR TOPICAL APPLICATION INCLUDING METABOLIC STABILITY, SOLUBILITY AND CELL PERMEABILITY. CONJUGATES WITH CRITERIA THAT EXCEED OR MATCH TRIVALINE-7269 WILL PROVIDE THE MINIMUM NUMBER OF ANALOGS FOR FUTURE DRUG DEVELOPMENT.

THE GRANTS TO SUPPORT FAMILIES IN THE JUSTICE SYSTEM PROGRAM (REFERRED TO AS THE JUSTICE FOR FAMILIES PROGRAM) WAS AUTHORIZED IN THE VIOLENCE AGAINST WOMEN REAUTHORIZATION ACT OF 2013 TO IMPROVE THE RESPONSE OF THE CIVIL AND CRIMINAL JUSTICE SYSTEM TO FAMILIES WITH A HISTORY OF DOMESTIC VIOLENCE, DATING VIOLENCE, SEXUAL ASSAULT, AND STALKING, OR IN CASES INVOLVING ALLEGATIONS OF CHILD SEXUAL ABUSE. THE PROGRAM SUPPORTS THE FOLLOWING ACTIVITIES FOR IMPROVING THE CAPACITY OF COURTS AND COMMUNITIES TO RESPOND TO FAMILIES AFFECTED BY THE TARGETED CRIMES: COURT-BASED AND COURT-RELATED PROGRAMS; SUPERVISED VISITATION AND SAFE EXCHANGE BY AND BETWEEN PARENTS; TRAINING FOR PEOPLE WHO WORK WITH FAMILIES IN THE COURT SYSTEM; CIVIL LEGAL SERVICES; AND THE PROVISION OF RESOURCES IN JUVENILE COURT MATTERS. PROJECTS SUPPORTED BY THE JUSTICE FOR FAMILIES PROGRAM ARE THOSE THAT FOCUS ON KEEPING VICTIMS AND THEIR CHILDREN SAFE FROM FURTHER ABUSE AND HOLDING OFFENDERS ACCOUNTABLE. THROUGH THIS CONTINUATION JUSTICE FOR FAMILIES PROJECT, THE JUSTICE & DIVERSITY CENTER OF THE BAR ASSOCIATION OF SAN FRANCISCO (JDC), IN PARTNERSHIP WITH THE COOPERATIVE RESTRAINING ORDER CLINIC (CROC), WOMEN ORGANIZED TO MAKE ABUSE XISTENT (WOMAN, INC.), AND THE SAN FRANCISCO SUPERIOR COURT, WILLPROVIDEINTAKE STAFF FOR THE SAN FRANCISCO SUPERIOR COURT CIVIL DOMESTIC VIOLENCE RESTRAINING ORDER CALENDARS; COURT RESOURCES TO UNREPRESENTED DOMESTIC VIOLENCE VICTIMS AT COURT HEARINGS; ADVOCACY TO VICTIMS OF DOMESTIC VIOLENCE; AND CIVIL LEGAL ASSISTANCE IN THE CITY AND COUNTY OF SAN FRANCISCO. THIS IS A CONTINUATION OF 15JOVW-22-GG-00227-JFFX.

PATHOGEN-SPECIFIC REGULATION OF PROTEIN ASSEMBLY

TRYPANOCIDAL AGENTS THAT KILL MULTIPLE STAGES OF THE TRYPANOSOMA CRUZI LIFE CYCLE

DEVELOPMENT OF FOSA INHIBITORS TO POTENTIATE FOSFOMYCIN ACTIVITY IN GRAM-NEGATIVE PATHOGENS - SUMMARY. ANTIMICROBIAL RESISTANCE IS WIDELY RECOGNIZED AS ONE OF THE MOST SIGNIFICANT PUBLIC HEALTH THREATS OF THE CENTURY. MANY BACTERIAL INFECTIONS HAVE BECOME DIFFICULT TO TREAT DUE TO ANTIMICROBIAL RESISTANCE, AND THERE IS AN URGENT NEED TO DEVELOP NEW STRATEGIES TO COMBAT THESE RESISTANT PATHOGENS. ONE SUCH STRATEGY IS TO REPOSITION OLDER ANTIBIOTICS THAT HAVE LONG-TRACK RECORDS OF SAFETY IN HUMAN. FOSFOMYCIN (FOM) IS AN ETABLISHED ANTIBIOTIC WHICH INACTIVATES UDP-N-ACETYLGLUCOSAMINE ENOLPYRUVYL TRANSFERASE IN BOTH GRAM-POSITIVE AND -NEGATIVE PATHOGENS. CURRENTLY, FOM IS EXCLUSIVELY USED AS AN ORAL FORMULATION FOR THE TREATMENT OF URINARY TRACT INFECTIONS GIVEN ITS EXCELLENT ACTIVITY AGAINST ESCHERICHIA COLI. HOWEVER, AN INTRAVENOUS FOM FORMULATION IS USED ELSEWHERE, AND IS CURRENTLY PENDING FDA APPROVAL IN U.S. FURTHERMORE, AN ONGOING NIAID-SPONSORED TRIAL (NCT03910673) IS EXPLORING WHETHER INTRAVENOUS FOM CAN EFFECTIVELY TREAT LUNG INFECTIONS, SUCH AS HOSPITAL-ACQUIRED AND VENTILATOR-ASSOCIATED BACTERIAL PNEUMONIA. FOSA IS A DIMERIC K+- AND MN2+-DEPENDENT GLUTATHIONE S-TRANSFERASE THAT CATALYZES THE NUCLEOPHILIC ADDITION OF GLUTATHIONE TO CARBON-1 IN THE EPOXIDE RING OF FOM, RENDERING THE ANTIBIOTIC INACTIVE. E. COLI LACKS INTRINSIC CHROMOSOMAL FOSA, THUS EXPLAINING ITS ACUTE SUSCEPTIBILITY TO FOM. HOWEVER, FOSA HOMOLOGUES ARE CHROMOSOMALLY ENCODED BY MANY GRAM-NEGATIVE SPECIES INCLUDING PSEUDOMONAS AERUGINOSA AND KLEBSIELLA PNEUMONIAE. OUR PRIOR RESEARCH HAS CLEARLY DEMONSTRATED THAT THIS INTRINSIC PRODUCTION OF FOSA CONFERS FOM RESISTANCE, AND THAT INACTIVATION OF FOSA PROVIDES A NOVEL APPROACH TO INCREASE THE SENSITIVITY OF CARBEPENEM RESISTANT GRAM-NEGATIVE PATHOGENS TO FOM, THUS HIGHLIGHTING A NOVEL PATHWAY TO EXPAND THE USE OF FOM TO A WIDE RANGE OF GRAM-NEGATIVE SPECIES. IMPORTANTLY, AND CENTRAL TO THIS APPLICATION, WE RECENTLY IDENTIFIED AND PATENTED A FIRST-IN-CLASS, COMPETITIVE SMALL MOLECULE INHIBITOR OF FOSA (ANY1) WHICH POTENTIATES FOM ACTIVITY AGAINST GRAM-NEGATIVE PATHOGENS THAT HARBOR THE FOSA GENE. USING INSIGHTS FROM THE ANY1-FOSA X-RAY CRYSTAL STRUCTURE, WE HAVE DESIGNED AND PREPARED AN ANALOG THAT HAS ~10X GREATER POTENCY, SHOWING THAT FURTHER SAR DEVELOPMENT IS POSSIBLE. THE AIMS IN THIS PROPOSAL ARE (1) MEDICINAL CHEMISTRY OPTIMIZATION OF FOSA INHIBITORS, (2) EVALUATION AND OPTIMIZATION OF ADME PROPERTIES, AND (3) BIOLOGICAL EVALUATION AGAINST A BROAD PANEL OF XDR GRAM-NEGATIVE CLINICAL ISOLATES. WE ANTICIPATE THAT SUCH A COMBINATION COULD BE USED TO TREAT INVASIVE INFECTIONS INCLUDING BACTEREMIA, PNEUMONIA, INTRA-ABDOMINAL INFECTIONS AND COMPLICATED UTIS CAUSED BY GRAM-NEGATIVE BACTERIA THAT HARBOR FOSA (E.G., K. PNEUMONIAE, ENTEROBACTER SPP., P. AERUGINOSA), INCLUDING EXTREMELY DRUG RESISTANT STRAINS. IN THIS PHASE I PROPOSAL, WE WILL IDENTIFY AND EVALUATE FOSA INHIBITORS BASED ON ANY1 BY COMBINING THE PHARMACEUTICAL AND MEDICINAL CHEMISTRY EXPERTISE OF THE SCIENTISTS AT THE FOX CHASE CHEMICAL DIVERSITY CENTER, INC. (FCCDC) WITH THE EXPERTISE AND EXPERIENCE OF THE SLUIS-CREMER LAB AT THE UNIVERSITY OF PITTSBURG IN THE EXPERIMENTAL ASPECTS OF FOSA INHIBITION AND ANTIBIOTIC THERAPY.

PROTACS AGAINST NEF AS A FUNCTIONAL CURE FOR HIV INFECTION

DEVELOPMENT OF SMALL MOLECULE THERAPEUTICS TARGETING HEMORRHAGIC FEVER VIRUSES

DEVELOPMENT OF HOST- ORIENTED THERAPEUTICS TARGETING SEVERE ACUTE RESPIRATORY SYNDROME CORONAVIRUS 2 (SARS-COV-2), - THE ULTIMATE GOAL OF THIS PHASE I APPLICATION IS TO DISCOVER AND DEVELOP HOST-ORIENTED SMALL MOLECULE COMPOUNDS TARGETING SEVERE ACUTE RESPIRATORY SYNDROME CORONAVIRUS 2 (SARS-COV-2) INFECTION. SARS-COV-2 IS A NOVEL CORONAVIRUS DRIVING THE CURRENT GLOBAL PANDEMIC OF SEVERE RESPIRATORY SYNDROME IN HUMANS. ANTIVIRAL THERAPEUTICS ARE URGENTLY NEEDED TO COMBAT INFECTION BY SARS-COV-2 AND NEW VARIANTS THAT ARE CONTINUING TO EMERGE. WE HAVE DISCOVERED SEVERAL CHEMICAL SERIES THAT TARGET MODULAR INTERACTIONS BETWEEN SPECIFIC HOST PROTEINS CONTAINING WW-DOMAINS (E.G. NEDD4) AND VIRAL PROTEINS CONTAINING PPXY MOTIFS (E.G. EBOLA VP40). NOTABLY, EMERGING RNA VIRUS PATHOGENS SUCH AS EBOLA, MARBURG, LASSA, AND RABIES VIRUSES ALL ENCODE PPXY MOTIFS THAT RECRUIT HOST WW-DOMAIN CONTAINING PROTEINS TO FACILITATE EFFICIENT VIRUS EGRESS, SPREAD, AND TRANSMISSION. INTERESTINGLY, THE SURFACE-EXPOSED SPIKE GLYCOPROTEIN (S) OF SARS-COV-2 ALSO HAS A PUTATIVE WW-DOMAIN BINDING MOTIF (25PPAY28), THAT IS NOT PRESENT IN THE S PROTEIN OF SARS-COV-1 OR MORE ATTENUATED CORONAVIRUS STRAINS. THE ACQUISITION OF THIS PPAY MOTIF IN THE MAJOR SURFACE PROTEIN OF SARS-COV-2 VIRIONS RAISES THE INTRIGUING POSSIBILITY THAT IT MAY CONTRIBUTE TO THE UNIQUE PATHOGENICITY AND/OR TRANSMISSION OF SARS-COV-2 VIA INTERACTIONS WITH SPECIFIC HOST WW-DOMAIN BEARING PROTEINS. IN OUR ONGOING STUDIES ON FILOVIRUSES AND ARENAVIRUSES, WE HAVE USED EXTENSIVE SAR TO IDENTIFY A LEAD COMPOUND SERIES CAPABLE OF BLOCKING EGRESS AND SPREAD OF LIVE EBOV, MARV, AND LAFV IN CELL CULTURE, AS WELL AS BLOCKING DISEASE PROGRESSION IN VIVO IN A LIVE MARV CHALLENGE MODEL. HERE, WE HYPOTHESIZE THAT “INFORMED” SAR ANALYSES OF OUR IN-HAND PPXY/WW-DOMAIN INHIBITORS (E.G. LEAD CANDIDATE FC-10696) WILL LEAD TO THE DISCOVERY OF ANALOGS CAPABLE OF BLOCKING EGRESS AND DISEASE PROGRESSION OF SARS-COV-2, AS WELL AS RELATED PPXY-CONTAINING VARIANTS THAT MAY EMERGE IN THE FUTURE. IN SUPPORT OF OUR HYPOTHESIS, WE PRESENT STRONG PRELIMINARY DATA SHOWING THAT THE PPXY MOTIF WITHIN THE S PROTEIN OF SARS-COV-2 VIRUS CAN INTERACT WITH HOST WW-DOMAIN CONTAINING PROTEINS THAT ARE KNOWN TO PROMOTE EGRESS AND SPREAD OF EBOV, MARV, AND LAFV. MOREOVER, OUR CURRENT LEAD CANDIDATE PPXY BUDDING INHIBITORS SHOW ACTIVITY IN BLOCKING EGRESS OF LIVE SARS-COV-2 VIRUS INFECTION IN HUMAN LUNG EPITHELIAL CELLS. IN THIS PHASE I PROPOSAL, WE WILL IDENTIFY AND EVALUATE HOST-ORIENTED INHIBITORS AS POTENTIAL THERAPEUTICS FOR SARS-COV-2 AND RELATED CORONAVIRUSES BY COMBINING THE PHARMACEUTICAL AND MEDICINAL CHEMISTRY EXPERTISE OF THE SCIENTISTS AT THE FOX CHASE CHEMICAL DIVERSITY CENTER, INC. (FCCDC) WITH THE EXPERTISE AND EXPERIENCE OF THE HARTY LAB AT THE UNIVERSITY OF PENNSYLVANIA IN THE EXPERIMENTAL ASPECTS OF VIRUS-HOST INTERACTIONS AND ANTIVIRAL THERAPY, AND THE LAB OF OLENA SHTANKO AT TEXAS BIOMEDICAL RESEARCH INSTITUTE FOR EVALUATING COMPOUNDS AGAINST LIVE VIRUSES UNDER BSL-3 CONDITIONS. THE THREE AIMS ARE (1) LEAD FINDING AND OPTIMIZATION MEDICINAL CHEMISTRY INCLUDING ADME PROFILING, (2) EVALUATION FOR THE ABILITY TO SPECIFICALLY INHIBIT EGRESS OF SARS-COV-2 VLPS AND PPXY- MEDIATED S-HOST PROTEIN INTERACTIONS, AND (3) IN VITRO AND IN VIVO ANALYSES AGAINST AUTHENTIC SARS-COV-2 VIRUS.

THE GRANTS TO SUPPORT FAMILIES IN THE JUSTICE SYSTEM PROGRAM (REFERRED TO AS THE JUSTICE FOR FAMILIES PROGRAM) WAS AUTHORIZED IN THE VIOLENCE AGAINST WOMEN REAUTHORIZATION ACT OF 2013 TO IMPROVE THE RESPONSE OF THE CIVIL AND CRIMINAL JUSTICE SYSTEM TO FAMILIES WITH A HISTORY OF DOMESTIC VIOLENCE, DATING VIOLENCE, SEXUAL ASSAULT, AND STALKING OR IN CASES INVOLVING ALLEGATIONS OF CHILD SEXUAL ABUSE. THE PROGRAM SUPPORTS THE FOLLOWING ACTIVITIES FOR IMPROVING THE CAPACITY OF COURTS AND COMMUNITIES TO RESPOND TO FAMILIES AFFECTED BY THE TARGETED CRIMES: COURT-BASED AND COURT-RELATED PROGRAMS; SUPERVISED VISITATION AND SAFE EXCHANGE BY AND BETWEEN PARENTS; TRAINING FOR PEOPLE WHO WORK WITH FAMILIES IN THE COURT SYSTEM; CIVIL LEGAL SERVICES; AND THE PROVISION OF RESOURCES IN JUVENILE COURT MATTERS. ALL PROJECTS UNDER THE JUSTICE FOR FAMILIES PROGRAM MUST ADDRESS SUPERVISED VISITATION OR COURT-BASED AND COURT-RELATED PROGRAMS.  IF A PROJECT IS ADDRESSING SUPERVISED VISITATION, IT MUST ALSO INCLUDE ACTIVITIES UNDER AT LEAST ONE ADDITIONAL PURPOSE AREA, SUCH AS CIVIL LEGAL SERVICES, COURT-BASED AND COURT-RELATED PROGRAMS, OR TRAINING WITHIN THE CIVIL JUSTICE SYSTEM. COURT-BASED AND COURT-RELATED PROGRAMS AND SERVICES MAY BE ADDRESSED ON THEIR OWN. PROJECTS SUPPORTED BY THE JUSTICE FOR FAMILIES PROGRAM FOCUS ON KEEPING VICTIMS AND THEIR CHILDREN SAFE FROM FURTHER ABUSE AND HOLDING OFFENDERS ACCOUNTABLE. ALL JUSTICE FOR FAMILIES PROGRAM PROJECTS MUST INCLUDE FORMAL PARTNERSHIPS WITH BOTH A NONPROFIT, NONGOVERNMENTAL, OR TRIBAL DOMESTIC VIOLENCE OR SEXUAL ASSAULT VICTIM SERVICE PROVIDER AND A COURT.   THE TIMING FOR PERFORMANCE OF THIS AWARD IS 36 MONTHS.

HOLISTIC EXPERT ADVOCACY AND LEGAL SERVICES FOR DOMESTIC VIOLENCE SURVIVORS (HEALS DV SURVIVORS)

THE LGBTQ+ COMMUNITY OF GREATER OKLAHOMA IS UNDER ATTACK. THIS COMMUNITY, LIKE OTHER MINORITY COMMUNITIES IN THE AREA AND ACROSS THE COUNTRY, IS SUFFERING FROM A DRASTIC RISE IN HATE CRIMES AND INCIDENTS, WHERE ITS MEMBERS HAVE BEEN TARGETED, ATTACKED, BULLIED, AND KILLED. THE DIVERSITY CENTER OF OKLAHOMA, INC. UNDERSTANDS THAT THE ONLY WAY TO PREVENT AND ADDRESS HATE CRIMES OF ANY KIND IS TO DEVELOP A WHOLE-COMMUNITY BASED APPROACH THAT ENCOMPASSES TRADITIONAL AND NON-TRADITIONAL PARTNER ORGANIZATIONS AND INVOLVES NEW AND INNOVATIVE OUTREACH, ENGAGEMENT, AND EDUCATIONAL PROGRAMS. THE PURPOSE OF THE COMMUNITY HATE CRIME PREVENTION PROGRAM IS TO CREATE NEW COMMUNITY-WIDE APPROACHES TO PREVENTING AND ADDRESSING HATE CRIMES IN ITS CATCHMENT AREA. PROJECT ACTIVITIES AND OUTCOMES INCLUDE WHOLE-COMMUNITY ENGAGEMENT ACTIVITIES WITH NON-TRADITIONAL PARTNER ORGANIZATIONS; NEW AND EASY-TO-USE METHODS TO REPORT HATE CRIMES AND INCIDENTS; NEW EDUCATIONAL PROGRAMMING WITH NON-TRADITIONAL PARTNERS, INCLUDING, BUT NOT LIMITED TO, THE EDUCATION SYSTEM, YOUTH, AND YOUNG ADULT GROUPS; AN ENHANCED RELATIONSHIP WITH OTHER TARGETED COMMUNITIES; ENGAGEMENT WITH THE WIDER CIVIC AND BUSINESS COMMUNITY; AND THE DEVELOPMENT OF A STANDING RELATIONSHIP WITH LAW ENFORCEMENT. THIS PROJECT WILL SEEK TO OBTAIN AND DEVELOP BETTER HATE CRIME AND HATE INCIDENT DATA, ENGAGE STAKEHOLDERS IN A COOPERATIVE AND JOINT MANNER, UTILIZE NATIONAL TRAINING EXPERTS IN THE REALM OF HATE CRIME PREVENTION, AND DEVELOP A STANDING TASK FORCE OF PARTNERS.

SAN FRANCISCO CIVIL DOMESTIC VIOLENCE COURT ENHANCEMENT PROJECT

THE PURPOSE OF THE LOW-INCOME TAXPAYER CLINIC LITC GRANT IS TO PROVIDE FINANCIAL ASSISTANCE TO, 1. A CLINICAL PROGRAM AT AN ACCREDITED LAW, BUSINESS, OR ACCOUNTING SCHOOL IN WHICH STUDENTS REPRESENT LOW-INCOME TAXPAYERS IN CONTROVERSIES ARISING UNDER IRC 7526. 2. AN ORGANIZATION DESCRIBED IN SECTION 501C AND EXEMPT FROM TAX UNDER SECTION 501A THROUGH REPRESENTATION OF TAXPAYERS OR REFERRAL OF TAXPAYERS TO QUALIFIED REPRESENTATIVES. ACTIVITIES TO BE PERFORMED UNDER THE LITC PROGRAM, THE INTERNAL REVENUE SERVICE AWARDS GRANTS SO THAT GRANT RECIPIENTS ARE ABLE TO PROVIDE TAX REPRESENTATION BEFORE THE INTERNAL REVENUE SERVICE OR OTHER TRIBUNAL ON FEDERAL TAX MATTERS, EDUCATIONAL ACTIVITIES ON VARIOUS TAX TOPICS AND ADVOCACY ON TAX ISSUES IMPACTING THE INTENDED BENEFICIARIES. END GOAL AND EXPECTED OUTCOMES, THE LITC PROGRAM AWARDS GRANTS TO, 1. OPEN NEW AND WORK PREVIOUSLY OPENED REPRESENTATION CASES. 2. CONSULT WITH TAXPAYERS ON THEIR SPECIFIC TAX ISSUE. 3. CONDUCT EDUCATIONAL ACTIVITIES. 4. MAKE CONTRIBUTIONS TO THE IMPROVEMENT TO TAX ADMINISTRATION BY ADVOCATING FOR CHANGES OR IMPROVEMENTS TO IRS ADMINISTRATION. INTENDED BENEFICIARIES, TAXPAYERS WITH INCOMES THAT DO NOT EXCEED 250 PERCENT OF THE FEDERAL POVERTY GUIDELINES AND TAXPAYERS FOR WHOM ENGLISH IS THEIR SECOND LANGUAGE. SUBRECIPIENT ACTIVITIES, IN LIMITED CIRCUMSTANCES AND WITH ADVANCED APPROVAL BY THE LITC PROGRAM OFFICE, SUBRECIPIENTS MAY BE UTILIZED BY GRANT RECIPIENTS TO HELP DELIVER KEY BROADBAND ELEMENTS OF THE PROGRAM. 5. REASON FOR MODIFICATION IF SHOWING A POSITIVE AMOUNT IS AN OBLIGATION FOR THE YEAR THAT IS REPRESENTED BY THE FIRST TWO DIGITS OF THE PRIME AWARD I.D., IF SHOWING A NEGATIVE AMOUNT IT IS A DE-OBLIGATION OR A RETURN OF FUNDS FOR THE YEAR REPRESENTED BY THE FIRST TWO DIGITS OF THE PRIME AWARD I.D.

DEVELOPMENT OF DRUGS THAT TARGET THE M2 PROTON CHANNEL FROM INFLUENZA A VIRUS

RILUZOLE PRODRUGS FOR MELANOMA AND ALS

OPTIMIZING A STAPLED-PEPTIDE THAT SPECIFICALLY TARGETS HSV-1 TO TREAT HERPES OCULAR KERATITIS

SOFT LXR AGONISTS FOR IDIOPATHIC PULMONARY FIBROSIS

SOFT LXR AGONISTS FOR THE TREATMENT OF IDIOPATHIC PULMONARY FIBROSIS

INHIBITORS OF THE PHD2 ZINC FINGER TO TREAT ANEMIA

PREGNANE X RECEPTOR (PXR) ANTAGONISTS FOR NON-ALCOHOLIC FATTY LIVER DISEASE

INHIBITORS OF HYDROGEN SULFIDE METABOLISM AS A NOVEL TREATMENT FOR HEART FAILURE

DISCOVERING A SMALL MOLECULE THAT TARGETS THE KSHV PROCESSIVITY FACTOR FOR TREATING ORAL AND SYSTEMIC KAPOSI SARCOMA

DEVELOPMENT OF SMALL MOLECULE THERAPEUTICS AGAINST RNA VIRUSES

NEW THERAPEUTICS FOR THE TREATMENT OF ACINETOBACTOR BAUMANNII INFECTIONS.

DC-SIGN INHIBITORS FOR THE TREATMENT OF HIV INFECTION

DEVELOPMENT OF A NOVEL ANTIVIRAL TO TREAT AND PREVENT ACYCLOVIR RESISTANCE IN HUMAN OCULAR HERPES KERATITIS

TRIGRILUZOLE FOR THE TREATMENT OF COCAINE ADDICTION

SMALL MOLECULE ANTAGONISTS OF PF4 FOR THE TREATMENT AND PREVENTION OF HIT

SMALL MOLECULE INHIBITORS OF HIV1 NEF VIRULENCE FACTOR FOR TREATMENT OF HIV_AIDS

THE PURPOSE OF THE LOW-INCOME TAXPAYER CLINIC LITC GRANT IS TO PROVIDE FINANCIAL ASSISTANCE TO, 1. A CLINICAL PROGRAM AT AN ACCREDITED LAW, BUSINESS, OR ACCOUNTING SCHOOL IN WHICH STUDENTS REPRESENT LOW-INCOME TAXPAYERS IN CONTROVERSIES ARISING UNDER IRC 7526. 2. AN ORGANIZATION DESCRIBED IN SECTION 501C AND EXEMPT FROM TAX UNDER SECTION 501A THROUGH REPRESENTATION OF TAXPAYERS OR REFERRAL OF TAXPAYERS TO QUALIFIED REPRESENTATIVES. ACTIVITIES TO BE PERFORMED UNDER THE LITC PROGRAM, THE INTERNAL REVENUE SERVICE AWARDS GRANTS SO THAT GRANT RECIPIENTS ARE ABLE TO PROVIDE TAX REPRESENTATION BEFORE THE INTERNAL REVENUE SERVICE OR OTHER TRIBUNAL ON FEDERAL TAX MATTERS, EDUCATIONAL ACTIVITIES ON VARIOUS TAX TOPICS AND ADVOCACY ON TAX ISSUES IMPACTING THE INTENDED BENEFICIARIES. END GOAL AND EXPECTED OUTCOMES, THE LITC PROGRAM AWARDS GRANTS TO, 1. OPEN NEW AND WORK PREVIOUSLY OPENED REPRESENTATION CASES. 2. CONSULT WITH TAXPAYERS ON THEIR SPECIFIC TAX ISSUE. 3. CONDUCT EDUCATIONAL ACTIVITIES. 4. MAKE CONTRIBUTIONS TO THE IMPROVEMENT TO TAX ADMINISTRATION BY ADVOCATING FOR CHANGES OR IMPROVEMENTS TO IRS ADMINISTRATION. INTENDED BENEFICIARIES, TAXPAYERS WITH INCOMES THAT DO NOT EXCEED 250 PERCENT OF THE FEDERAL POVERTY GUIDELINES AND TAXPAYERS FOR WHOM ENGLISH IS THEIR SECOND LANGUAGE. SUBRECIPIENT ACTIVITIES, IN LIMITED CIRCUMSTANCES AND WITH ADVANCED APPROVAL BY THE LITC PROGRAM OFFICE, SUBRECIPIENTS MAY BE UTILIZED BY GRANT RECIPIENTS TO HELP DELIVER KEY BROADBAND ELEMENTS OF THE PROGRAM. 5. REASON FOR MODIFICATION IF SHOWING A POSITIVE AMOUNT IS AN OBLIGATION FOR THE YEAR THAT IS REPRESENTED BY THE FIRST TWO DIGITS OF THE PRIME AWARD I.D., IF SHOWING A NEGATIVE AMOUNT IT IS A DE-OBLIGATION OR A RETURN OF FUNDS FOR THE YEAR REPRESENTED BY THE FIRST TWO DIGITS OF THE PRIME AWARD I.D.

THE PURPOSE OF THE LOW-INCOME TAXPAYER CLINIC LITC GRANT IS TO PROVIDE FINANCIAL ASSISTANCE TO, 1. A CLINICAL PROGRAM AT AN ACCREDITED LAW, BUSINESS, OR ACCOUNTING SCHOOL IN WHICH STUDENTS REPRESENT LOW-INCOME TAXPAYERS IN CONTROVERSIES ARISING UNDER IRC 7526. 2. AN ORGANIZATION DESCRIBED IN SECTION 501C AND EXEMPT FROM TAX UNDER SECTION 501A THROUGH REPRESENTATION OF TAXPAYERS OR REFERRAL OF TAXPAYERS TO QUALIFIED REPRESENTATIVES. ACTIVITIES TO BE PERFORMED UNDER THE LITC PROGRAM, THE INTERNAL REVENUE SERVICE AWARDS GRANTS SO THAT GRANT RECIPIENTS ARE ABLE TO PROVIDE TAX REPRESENTATION BEFORE THE INTERNAL REVENUE SERVICE OR OTHER TRIBUNAL ON FEDERAL TAX MATTERS, EDUCATIONAL ACTIVITIES ON VARIOUS TAX TOPICS AND ADVOCACY ON TAX ISSUES IMPACTING THE INTENDED BENEFICIARIES. END GOAL AND EXPECTED OUTCOMES, THE LITC PROGRAM AWARDS GRANTS TO, 1. OPEN NEW AND WORK PREVIOUSLY OPENED REPRESENTATION CASES. 2. CONSULT WITH TAXPAYERS ON THEIR SPECIFIC TAX ISSUE. 3. CONDUCT EDUCATIONAL ACTIVITIES. 4. MAKE CONTRIBUTIONS TO THE IMPROVEMENT TO TAX ADMINISTRATION BY ADVOCATING FOR CHANGES OR IMPROVEMENTS TO IRS ADMINISTRATION. INTENDED BENEFICIARIES, TAXPAYERS WITH INCOMES THAT DO NOT EXCEED 250 PERCENT OF THE FEDERAL POVERTY GUIDELINES AND TAXPAYERS FOR WHOM ENGLISH IS THEIR SECOND LANGUAGE. SUBRECIPIENT ACTIVITIES, IN LIMITED CIRCUMSTANCES AND WITH ADVANCED APPROVAL BY THE LITC PROGRAM OFFICE, SUBRECIPIENTS MAY BE UTILIZED BY GRANT RECIPIENTS TO HELP DELIVER KEY BROADBAND ELEMENTS OF THE PROGRAM. 5. REASON FOR MODIFICATION IF SHOWING A POSITIVE AMOUNT IS AN OBLIGATION FOR THE YEAR THAT IS REPRESENTED BY THE FIRST TWO DIGITS OF THE PRIME AWARD I.D., IF SHOWING A NEGATIVE AMOUNT IT IS A DEOBLIGATION OR A RETURN OF FUNDS FOR THE YEAR REPRESENTED BY THE FIRST TWO DIGITS OF THE PRIME AWARD I.D.

THE PURPOSE OF THE LOW-INCOME TAXPAYER CLINIC LITC GRANT IS TO PROVIDE FINANCIAL ASSISTANCE TO, 1. A CLINICAL PROGRAM AT AN ACCREDITED LAW, BUSINESS, OR ACCOUNTING SCHOOL IN WHICH STUDENTS REPRESENT LOW-INCOME TAXPAYERS IN CONTROVERSIES ARISING UNDER IRC 7526. 2. AN ORGANIZATION DESCRIBED IN SECTION 501C AND EXEMPT FROM TAX UNDER SECTION 501A THROUGH REPRESENTATION OF TAXPAYERS OR REFERRAL OF TAXPAYERS TO QUALIFIED REPRESENTATIVES. ACTIVITIES TO BE PERFORMED UNDER THE LITC PROGRAM, THE INTERNAL REVENUE SERVICE AWARDS GRANTS SO THAT GRANT RECIPIENTS ARE ABLE TO PROVIDE TAX REPRESENTATION BEFORE THE INTERNAL REVENUE SERVICE OR OTHER TRIBUNAL ON FEDERAL TAX MATTERS, EDUCATIONAL ACTIVITIES ON VARIOUS TAX TOPICS AND ADVOCACY ON TAX ISSUES IMPACTING THE INTENDED BENEFICIARIES. END GOAL AND EXPECTED OUTCOMES, THE LITC PROGRAM AWARDS GRANTS TO, 1. OPEN NEW AND WORK PREVIOUSLY OPENED REPRESENTATION CASES. 2. CONSULT WITH TAXPAYERS ON THEIR SPECIFIC TAX ISSUE. 3. CONDUCT EDUCATIONAL ACTIVITIES. 4. MAKE CONTRIBUTIONS TO THE IMPROVEMENT TO TAX ADMINISTRATION BY ADVOCATING FOR CHANGES OR IMPROVEMENTS TO IRS ADMINISTRATION. INTENDED BENEFICIARIES, TAXPAYERS WITH INCOMES THAT DO NOT EXCEED 250 PERCENT OF THE FEDERAL POVERTY GUIDELINES AND TAXPAYERS FOR WHOM ENGLISH IS THEIR SECOND LANGUAGE. SUBRECIPIENT ACTIVITIES, IN LIMITED CIRCUMSTANCES AND WITH ADVANCED APPROVAL BY THE LITC PROGRAM OFFICE, SUBRECIPIENTS MAY BE UTILIZED BY GRANT RECIPIENTS TO HELP DELIVER KEY BROADBAND ELEMENTS OF THE PROGRAM. 5. REASON FOR MODIFICATION IF SHOWING A POSITIVE AMOUNT IS AN OBLIGATION FOR THE YEAR THAT IS REPRESENTED BY THE FIRST TWO DIGITS OF THE PRIME AWARD I.D., IF SHOWING A NEGATIVE AMOUNT IT IS A DE-OBLIGATION OR A RETURN OF FUNDS FOR THE YEAR REPRESENTED BY THE FIRST TWO DIGITS OF THE PRIME AWARD I.D.

THE PURPOSE OF THIS GRANT PROGRAM IS TO PROVIDE CULTURALLY RESPONSIVE SERVICES TO CRIME VICTIMS AND SURVIVORS FROM COMMUNITIES THAT HAVE BEEN HISTORICALLY UNDERSERVED; MARGINALIZED; ADVERSELY AFFECTED BY INEQUALITY; AND DISPROPORTIONATELY IMPACTED BY CRIME, VIOLENCE, AND VICTIMIZATION. WITH THIS FUNDING, DIVERSITY CENTER OF OKLAHOMA, INC., WILL PROVIDE HOLISTIC COMMUNITY AND CULTURALLY SPECIFIC INTIMATE PARTNER VIOLENCE PREVENTION AND INTERVENTION SERVICES FOR GENDER AND SEXUAL MINORITIES, SPECIFICALLY BLACK AND BROWN WOMEN, INCLUDING BLACK TRANSGENDER WOMEN. SERVICES WILL BE PROVIDED PRIMARILY IN OKLAHOMA CITY AND FOLSOM METRO AREAS AND THROUGHOUT OKLAHOMA AS NEEDED. SERVICES TO BE PROVIDED WILL INCLUDE ADVOCACY, LEGAL SERVICES, GENDER AFFIRMING MEDICAL CARE, COUNSELING, BEHAVIORAL HEALTH, PEER SUPPORT GROUPS, FINANCIAL LITERACY, EDUCATION AND CAREER SERVICES, PARENTING CLASSES, HOUSING ASSISTANCE, AND TRANSPORTATION.

THE PURPOSE OF THE LOW-INCOME TAXPAYER CLINIC LITC GRANT IS TO PROVIDE FINANCIAL ASSISTANCE TO, 1. A CLINICAL PROGRAM AT AN ACCREDITED LAW, BUSINESS, OR ACCOUNTING SCHOOL IN WHICH STUDENTS REPRESENT LOW-INCOME TAXPAYERS IN CONTROVERSIES ARISING UNDER IRC 7526. 2. AN ORGANIZATION DESCRIBED IN SECTION 501C AND EXEMPT FROM TAX UNDER SECTION 501A THROUGH REPRESENTATION OF TAXPAYERS OR REFERRAL OF TAXPAYERS TO QUALIFIED REPRESENTATIVES. ACTIVITIES TO BE PERFORMED UNDER THE LITC PROGRAM, THE INTERNAL REVENUE SERVICE AWARDS GRANTS SO THAT GRANT RECIPIENTS ARE ABLE TO PROVIDE TAX REPRESENTATION BEFORE THE INTERNAL REVENUE SERVICE OR OTHER TRIBUNAL ON FEDERAL TAX MATTERS, EDUCATIONAL ACTIVITIES ON VARIOUS TAX TOPICS AND ADVOCACY ON TAX ISSUES IMPACTING THE INTENDED BENEFICIARIES. END GOAL AND EXPECTED OUTCOMES, THE LITC PROGRAM AWARDS GRANTS TO, 1. OPEN NEW AND WORK PREVIOUSLY OPENED REPRESENTATION CASES. 2. CONSULT WITH TAXPAYERS ON THEIR SPECIFIC TAX ISSUE. 3. CONDUCT EDUCATIONAL ACTIVITIES. 4. MAKE CONTRIBUTIONS TO THE IMPROVEMENT TO TAX ADMINISTRATION BY ADVOCATING FOR CHANGES OR IMPROVEMENTS TO IRS ADMINISTRATION. INTENDED BENEFICIARIES, TAXPAYERS WITH INCOMES THAT DO NOT EXCEED 250 PERCENT OF THE FEDERAL POVERTY GUIDELINES AND TAXPAYERS FOR WHOM ENGLISH IS THEIR SECOND LANGUAGE. SUBRECIPIENT ACTIVITIES, IN LIMITED CIRCUMSTANCES AND WITH ADVANCED APPROVAL BY THE LITC PROGRAM OFFICE, SUBRECIPIENTS MAY BE UTILIZED BY GRANT RECIPIENTS TO HELP DELIVER KEY BROADBAND ELEMENTS OF THE PROGRAM. 5. REASON FOR MODIFICATION IF SHOWING A POSITIVE AMOUNT IS AN OBLIGATION FOR THE YEAR THAT IS REPRESENTED BY THE FIRST TWO DIGITS OF THE PRIME AWARD I.D., IF SHOWING A NEGATIVE AMOUNT IT IS A DEOBLIGATION OR A RETURN OF FUNDS FOR THE YEAR REPRESENTED BY THE FIRST TWO DIGITS OF THE PRIME AWARD I.D.

THE PURPOSE OF THE LOW-INCOME TAXPAYER CLINIC LITC GRANT IS TO PROVIDE FINANCIAL ASSISTANCE TO, 1. A CLINICAL PROGRAM AT AN ACCREDITED LAW, BUSINESS, OR ACCOUNTING SCHOOL IN WHICH STUDENTS REPRESENT LOW-INCOME TAXPAYERS IN CONTROVERSIES ARISING UNDER IRC 7526. 2. AN ORGANIZATION DESCRIBED IN SECTION 501C AND EXEMPT FROM TAX UNDER SECTION 501A THROUGH REPRESENTATION OF TAXPAYERS OR REFERRAL OF TAXPAYERS TO QUALIFIED REPRESENTATIVES. ACTIVITIES TO BE PERFORMED UNDER THE LITC PROGRAM, THE INTERNAL REVENUE SERVICE AWARDS GRANTS SO THAT GRANT RECIPIENTS ARE ABLE TO PROVIDE TAX REPRESENTATION BEFORE THE INTERNAL REVENUE SERVICE OR OTHER TRIBUNAL ON FEDERAL TAX MATTERS, EDUCATIONAL ACTIVITIES ON VARIOUS TAX TOPICS AND ADVOCACY ON TAX ISSUES IMPACTING THE INTENDED BENEFICIARIES. END GOAL AND EXPECTED OUTCOMES, THE LITC PROGRAM AWARDS GRANTS TO, 1. OPEN NEW AND WORK PREVIOUSLY OPENED REPRESENTATION CASES. 2. CONSULT WITH TAXPAYERS ON THEIR SPECIFIC TAX ISSUE. 3. CONDUCT EDUCATIONAL ACTIVITIES. 4. MAKE CONTRIBUTIONS TO THE IMPROVEMENT TO TAX ADMINISTRATION BY ADVOCATING FOR CHANGES OR IMPROVEMENTS TO IRS ADMINISTRATION. INTENDED BENEFICIARIES, TAXPAYERS WITH INCOMES THAT DO NOT EXCEED 250 PERCENT OF THE FEDERAL POVERTY GUIDELINES AND TAXPAYERS FOR WHOM ENGLISH IS THEIR SECOND LANGUAGE. SUBRECIPIENT ACTIVITIES, IN LIMITED CIRCUMSTANCES AND WITH ADVANCED APPROVAL BY THE LITC PROGRAM OFFICE, SUBRECIPIENTS MAY BE UTILIZED BY GRANT RECIPIENTS TO HELP DELIVER KEY BROADBAND ELEMENTS OF THE PROGRAM. 5. REASON FOR MODIFICATION IF SHOWING A POSITIVE AMOUNT IS AN OBLIGATION FOR THE YEAR THAT IS REPRESENTED BY THE FIRST TWO DIGITS OF THE PRIME AWARD I.D., IF SHOWING A NEGATIVE AMOUNT IT IS A DEOBLIGATION OR A RETURN OF FUNDS FOR THE YEAR REPRESENTED BY THE FIRST TWO DIGITS OF THE PRIME AWARD I.D.

THE PURPOSE OF THE LOW-INCOME TAXPAYER CLINIC LITC GRANT IS TO PROVIDE FINANCIAL ASSISTANCE TO, 1. A CLINICAL PROGRAM AT AN ACCREDITED LAW, BUSINESS, OR ACCOUNTING SCHOOL IN WHICH STUDENTS REPRESENT LOW-INCOME TAXPAYERS IN CONTROVERSIES ARISING UNDER IRC 7526. 2. AN ORGANIZATION DESCRIBED IN SECTION 501C AND EXEMPT FROM TAX UNDER SECTION 501A THROUGH REPRESENTATION OF TAXPAYERS OR REFERRAL OF TAXPAYERS TO QUALIFIED REPRESENTATIVES. ACTIVITIES TO BE PERFORMED UNDER THE LITC PROGRAM, THE INTERNAL REVENUE SERVICE AWARDS GRANTS SO THAT GRANT RECIPIENTS ARE ABLE TO PROVIDE TAX REPRESENTATION BEFORE THE INTERNAL REVENUE SERVICE OR OTHER TRIBUNAL ON FEDERAL TAX MATTERS, EDUCATIONAL ACTIVITIES ON VARIOUS TAX TOPICS AND ADVOCACY ON TAX ISSUES IMPACTING THE INTENDED BENEFICIARIES. END GOAL AND EXPECTED OUTCOMES, THE LITC PROGRAM AWARDS GRANTS TO, 1. OPEN NEW AND WORK PREVIOUSLY OPENED REPRESENTATION CASES. 2. CONSULT WITH TAXPAYERS ON THEIR SPECIFIC TAX ISSUE. 3. CONDUCT EDUCATIONAL ACTIVITIES. 4. MAKE CONTRIBUTIONS TO THE IMPROVEMENT TO TAX ADMINISTRATION BY ADVOCATING FOR CHANGES OR IMPROVEMENTS TO IRS ADMINISTRATION. INTENDED BENEFICIARIES, TAXPAYERS WITH INCOMES THAT DO NOT EXCEED 250 PERCENT OF THE FEDERAL POVERTY GUIDELINES AND TAXPAYERS FOR WHOM ENGLISH IS THEIR SECOND LANGUAGE. SUBRECIPIENT ACTIVITIES, IN LIMITED CIRCUMSTANCES AND WITH ADVANCED APPROVAL BY THE LITC PROGRAM OFFICE, SUBRECIPIENTS MAY BE UTILIZED BY GRANT RECIPIENTS TO HELP DELIVER KEY BROADBAND ELEMENTS OF THE PROGRAM. 5. REASON FOR MODIFICATION IF SHOWING A POSITIVE AMOUNT IS AN OBLIGATION FOR THE YEAR THAT IS REPRESENTED BY THE FIRST TWO DIGITS OF THE PRIME AWARD I.D., IF SHOWING A NEGATIVE AMOUNT IT IS A DEOBLIGATION OR A RETURN OF FUNDS FOR THE YEAR REPRESENTED BY THE FIRST TWO DIGITS OF THE PRIME AWARD I.D.

THE PURPOSE OF THE LOW-INCOME TAXPAYER CLINIC LITC GRANT IS TO PROVIDE FINANCIAL ASSISTANCE TO, 1. A CLINICAL PROGRAM AT AN ACCREDITED LAW, BUSINESS, OR ACCOUNTING SCHOOL IN WHICH STUDENTS REPRESENT LOW-INCOME TAXPAYERS IN CONTROVERSIES ARISING UNDER IRC 7526. 2. AN ORGANIZATION DESCRIBED IN SECTION 501C AND EXEMPT FROM TAX UNDER SECTION 501A THROUGH REPRESENTATION OF TAXPAYERS OR REFERRAL OF TAXPAYERS TO QUALIFIED REPRESENTATIVES. ACTIVITIES TO BE PERFORMED UNDER THE LITC PROGRAM, THE INTERNAL REVENUE SERVICE AWARDS GRANTS SO THAT GRANT RECIPIENTS ARE ABLE TO PROVIDE TAX REPRESENTATION BEFORE THE INTERNAL REVENUE SERVICE OR OTHER TRIBUNAL ON FEDERAL TAX MATTERS, EDUCATIONAL ACTIVITIES ON VARIOUS TAX TOPICS AND ADVOCACY ON TAX ISSUES IMPACTING THE INTENDED BENEFICIARIES. END GOAL AND EXPECTED OUTCOMES, THE LITC PROGRAM AWARDS GRANTS TO, 1. OPEN NEW AND WORK PREVIOUSLY OPENED REPRESENTATION CASES. 2. CONSULT WITH TAXPAYERS ON THEIR SPECIFIC TAX ISSUE. 3. CONDUCT EDUCATIONAL ACTIVITIES. 4. MAKE CONTRIBUTIONS TO THE IMPROVEMENT TO TAX ADMINISTRATION BY ADVOCATING FOR CHANGES OR IMPROVEMENTS TO IRS ADMINISTRATION. INTENDED BENEFICIARIES, TAXPAYERS WITH INCOMES THAT DO NOT EXCEED 250 PERCENT OF THE FEDERAL POVERTY GUIDELINES AND TAXPAYERS FOR WHOM ENGLISH IS THEIR SECOND LANGUAGE. SUBRECIPIENT ACTIVITIES, IN LIMITED CIRCUMSTANCES AND WITH ADVANCED APPROVAL BY THE LITC PROGRAM OFFICE, SUBRECIPIENTS MAY BE UTILIZED BY GRANT RECIPIENTS TO HELP DELIVER KEY BROADBAND ELEMENTS OF THE PROGRAM. 5. REASON FOR MODIFICATION IF SHOWING A POSITIVE AMOUNT IS AN OBLIGATION FOR THE YEAR THAT IS REPRESENTED BY THE FIRST TWO DIGITS OF THE PRIME AWARD I.D., IF SHOWING A NEGATIVE AMOUNT IT IS A DEOBLIGATION OR A RETURN OF FUNDS FOR THE YEAR REPRESENTED BY THE FIRST TWO DIGITS OF THE PRIME AWARD I.D.

JDC LOW INCOME TAXPAYER CLINIC

JDC LOW INCOME TAXPAYER CLINIC

LOW INCOME TAXPAYER CLINIC

LOW INCOME TAXPAYER CLINIC

LOW INCOME TAXPAYER CLINIC

LOW INCOME TAXPAYER CLINIC

LOW INCOME TAXPAYER CLINIC

LOW INCOME TAXPAYER CLINIC

LOW INCOME TAXPAYER CLINIC

LOW INCOME TAXPAYER CLINIC

SHELTER AND SERVICES PROGRAM