A single antiviral to treat multiple opportunistic infections

单一抗病毒药物可治疗多种机会性感染

• 批准号: 10218021
• 负责人: Stacy Remiszewski
• 金额: $ 100万
• 依托单位: EVRYS BIO, LLC
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-15 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10218021
• 关键词: Absorbable Gelatin Sponge; Address; Adenoviruses; Affect; American; Animal Model; Antibiotics; Antipsychotic Agents; Antiviral Agents; Asthma; Biological Availability; Biological Sciences; Cavia; Cell physiology; Cells; Chemicals; Chemistry; Communities; Cytomegalovirus; Data; Detection; Development; Disease; Dose; Drug Exposure; Drug Interactions; Drug Targeting; Drug resistance; Effectiveness; Enzymes; Exposure to; Family; Fibroblasts; Ganciclovir; Goals; Graft Rejection; Growth; HIV; Hematopoietic Stem Cell Transplantation; Hepatitis B; Hepatitis B Virus; Hepatitis C virus; Hepatitis Viruses; Herpesviridae; Herpesvirus 1; Human; Immune system; Immunity; Immunosuppression; Implant; In Vitro; Individual; Infection; Influenza A virus; Influenza B Virus; Intravenous; Investigational Drugs; Lead; Life; Measures; Mission; Modeling; Morbidity - disease rate; Mus; Opportunistic Infections; Oral; Organ; Organ Transplantation; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Polyomavirus; Primary Infection; Problem Solving; Production; Prophylactic treatment; Proteins; Regimen; Reproducibility; Resistance; Resistance development; Rhesus; Rheumatism; Risk; Route; SCID Mice; Series; Sirtuins; Small Business Innovation Research Grant; Structure of parenchyma of lung; Structure-Activity Relationship; Technology; Therapeutic; Therapeutic Index; Therapeutic Intervention; Therapeutic immunosuppression; Time; Toxicity Tests; Transplant Recipients; Transplantation; Triage; Universities; Valganciclovir; Validation; Vasoconstrictor Agents; Viral; Viral Drug Resistance; Viral Proteins; Virus; Virus Diseases; Virus Latency; Virus Replication; acquired drug resistance; base; candidate validation; clinical development; commercialization; expectation; good laboratory practice; high risk; immunosuppressed; improved; in vivo; inhibitor/antagonist; lead optimization; minimal risk; mortality; mouse model; nephrotoxicity; next generation; novel; pathogen; penis foreskin; post-transplant; pre-clinical; preclinical development; programs; resistance mutation; resistant strain; respiratory virus; side effect; small molecule; standard of care; synergism; viral resistance

Current standard-of-care antiviral regimens rely on direct-acting antivirals (DAAs) possessing inherent liabilities. DAAs are generally active against only one virus or a closely related, family of viruses. Because a viral protein is targeted, the virus can readily develop resistance mutations. To address the shortcomings of DAAs, FORGE Life Science is developing host-targeted antivirals (HTAs). HTAs have the potential to block the growth of multiple different viruses. Since a host-cell protein is targeted, viruses are much less likely to evolve drug resistance. Specifically, FORGE is developing small molecule drugs that target human sirtuin proteins. Sirtuins are a family of seven protein-deacylases that modulate many cellular processes critical for virus replication. This proposal seeks to develop a sirtuin-modulating drug that is simultaneously effective against multiple different opportunistic viruses causing life-threatening disease in immunosuppressed transplant patients. Initially, the program is focused on human cytomegalovirus (HCMV). In Phase 1, a chemical series of uncompetitive sirtuin 2 (SIRT2) inhibitors was developed that block the production of HCMV progeny in cultured human cells more potently than standard-of-care, ganciclovir. Strikingly, these SIRT2 inhibitors not only affect HCMV, but they also inhibited the growth of influenza A and B, hepatitis B and C viruses, and the polyomaviruses, BKV and JCV. The compound series demonstrates structure activity relationship to antiviral potency, excellent oral bioavailability, and good tolerability in mice. In vivo validation of anti-HCMV activity was achieved in immunosuppressed mice carrying human lung-tissue implants. This application proposes to move the program forward to SBIR Phase II to optimize a development candidate for progression into preclinical development. Three aims will be pursued. (1) A mouse model supporting development of recently approved DAA letermovir will be adapted for use with SIRT2 inhibitors. This model allows for HCMV infection of human fibroblasts seeded to a Gelfoam implant placed into immunodeficient SCID mice. (2) A medicinal chemistry campaign will refine the current lead SIRT2 inhibitor to improve anti-HCMV activity in the Gelfoam/SCID mouse with a target to achieve a therapeutic index equivalent or better than oral-dosing valganciclovir and letermovir. The selected development candidate will additionally satisfy in vitro ADME and pharmaceutical criteria, including minimizing drug-drug interactions, for administration to transplant patients. (3) Compounds demonstrating sufficient efficacy in the Gelfoam/SCID mouse model will be validated with respect to providing a high barrier to acquired viral drug-resistance and to synergize with existing direct-acting antivirals. The pan-viral profile will be expanded to multiple opportunistic viruses. This project has the potential to produce a paradigm shift, introducing broad-spectrum antivirals that solve the problem of viral resistance.

目前的标准抗病毒治疗方案依赖于直接作用抗病毒药物（DAAs），这些药物具有固有的副作用。