This revised application is for a Phase I SBIR grant under PA-17-302 in which NIAID and DAIDS have expressed a special emphasis on the development of anti-HIV agents directed at new viral or cellular targets for treatment of HIV infection. The goal of our proposal is to address the call to evaluate novel drug targets by conducting preclinical studies for a first-in- class antiretroviral (ARV) therapeutic for which we have obtained a strong foundation for mechanism of action (MOA) through lead development of an HIV-1 (HIV) Vif antagonist. The compounds described herein enable the host cell factors APOBEC3G (A3G) and APOBEC3F (A3F) involved in innate immunity to broadly neutralize HIV through APOBEC-dependent hypermutation of viral genomes during reverse transcription. We have conducted medicinal chemistry to optimize leads with increased efficacy in the single-digit nanomolar range against HIV isolates from clades A, B and C. Since the initial submission of this proposal we also have comprised a prodrug strategy to increase plasma half-life in vivo and chemical synthesis for both the lead, SN38-L and prodrug, Irino-L, have been optimized. Moreover, ADMET studies revealed promising parameters and have addressed the initial reviewers concerns of toxicity. Based on reviewer recommendations this SBIR proposal now seeks to prioritize detailed pharmacokinetic (PK) studies, humanized mice in vivo efficacy studies, and viral resistance studies. As requested by the reviewers, studies required by the FDA under the Guidance for Industry Antiviral Product Development: Conducting and Submitting Virology Studies to the Agency have been moved to Phase II.
Public Health Relevance Statement: PROJECT NARRATIVE The revised SBIR Phase I proposal addresses the RFA call for novel drugs on novel viral targets that will address HIV drug resistance and the potential for a cure. APOBEC3G (A3G) is an antiviral protein found in human white blood cells that inhibits viral replication by inducing mutations in the HIV viral genome and causing it to fail during replication. However, as its own defense, HIV expresses the Vif protein that binds to A3G and thereby triggers its elimination by the hosts intracellular protein digestion machinery. Despite significant academic research, there is an unmet need to identify small molecular antagonists of Vif with a validated mechanism of action that have clinical potential. We have identified a highly potent Vif antagonist as a broadly neutralizing antiviral lead candidate for preclinical development that has been validated by third parties. The proposed Phase I studies will produce preclinical and IND-enabling data essential for regulatory approval and clinical trials for a first-in-class therapeutic and an opportunity to explore its curative potential.
NIH Spending Category: Antimicrobial Resistance; Biotechnology; Clinical Research; Clinical Trials and Supportive Activities; HIV/AIDS; Infectious Diseases
Project Terms: Address; analog; Animals; Anti-HIV Agents; Anti-Retroviral Agents; anti-viral efficacy; Antiviral Agents; APOBEC3F gene; APOCEC3G gene; base; Binding Proteins; Biological Availability; Biological Models; Cells; cellular targeting; chemical synthesis; Clinical; Clinical Trials; Data; Development; Digestion; Digit structure; Dose; Drug Kinetics; Drug resistance; druggable target; efficacy study; Formulation; Foundations; Goals; Grant; Half-Life; HIV; HIV drug resistance; HIV Infections; HIV-1; Hour; Human; Human immunodeficiency virus test; humanized mouse; improved; in vivo; in vivo evaluation; in vivo Model; Induced Mutation; Industry; inhibitor/antagonist; insight; irinotecan; Lactones; Lead; lead candidate; Leukocytes; Molecular; Monitor; mouse model; Mutation; nanomolar; National Institute of Allergy and Infectious Disease; Natural Immunity; new therapeutic target; novel; novel therapeutics; Oral; particle; Pathway interactions; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; phase 1 study; phase 2 study; Phase I Clinical Trials; Plasma; pre-clinical; preclinical development; preclinical study; Prodrugs; product development; Proteins; Publications; Publishing; Recommendation; Reporting; Research; Resistance; Reverse Transcription; screening; Serum; Small Business Innovation Research Grant; Testing; Therapeutic; Toxic effect; uptake; Validation; vif Gene Products; Viral; Viral Genome; viral resistance; virology; Virus; Virus Replication
