Ultrapotent Inhibitors of Wild-type and Multi-drug Resistant HIV

野生型和多重耐药艾滋病毒的超强抑制剂

• 批准号: 10550260
• 负责人: Stefan G Sarafianos
• 金额: $ 47.05万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-05 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10550260
• 关键词: 2' -deoxyadenosine; Acquired Immunodeficiency Syndrome; Action Potentials; Address; Adherence; Affect; Animal Model; Anti-HIV Agents; Antiviral Agents; Belief; Binding; Binding Sites; Biochemical; Biological Assay; Cell Culture Techniques; Cell Line; Cells; Chronic; Clinic; Clinical; Combined Modality Therapy; Complex; Data; Development; Dose; Drug Combinations; Drug resistance; Event; Excision; Funding; Generations; Genomics; Guidelines; HIV; HIV Infections; HIV drug resistance; HIV resistance; HIV therapy; In Vitro; Licensing; Modality; Multi-Drug Resistance; Mus; Mutation; Names; Nucleosides; Nucleotides; Oral; Outcome; Paper; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Phase; Phase II Clinical Trials; Prevention; Publishing; RNA-Directed DNA Polymerase; Research; Resistance; Resistance profile; Reverse Transcriptase Inhibitors; Reverse Transcription; Site; Structure; System; Tenofovir; Testing; Time; United States National Institutes of Health; Vertebral column; Viral; Virus; Work; Zidovudine; analog; antiretroviral therapy; cell immortalization; design; drug resistant virus; experimental study; inhibitor; inhibitor therapy; innovation; insight; mutant; next generation; next generation sequencing; non-nucleoside reverse transcriptase inhibitors; nonhuman primate; novel; novel therapeutics; nucleoside analog; optimal treatments; preclinical development; reconstitution; resistance mutation; viral DNA

PROJECT SUMMARY Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) efficiently suppress HIV and serve as backbone of antiretroviral therapies. However, new therapeutics are needed for continued control of HIV infection. 4’- Ethynyl-2-fluoro-2’-deoxyadenosine (EFdA) is an NRTI with exceptional potency, stability, and unique mechanism of action against HIV, which has been licensed by Merck. EFdA (also known as MK-8591 or Islatavir) has been successfully used in Phase I and recently introduced in Phase II clinical trials. EFdA has generated “compelling early results for both treatment and prevention” in patients, tested at remarkably low doses (up to >10,000-fold lower doses than current NRTI drugs) aiming at once-weekly oral and once-yearly slow-release dosing, unprecedented modalities for HIV therapies. Hence, this work is directly relevant to NIH guidelines for high priority AIDS funding (NOT-OD-15-137) for “next generation therapies…that are longer acting.” We have shown that a) EFdA has high potency in vitro, in cell culture (EC50=50 pM in PBMCs), mice and non- human primate animal models. Although EFdA retains the 3’-OH, it blocks HIV reverse transcriptase (RT) in vitro, primarily as an immediate/obligate and at times delayed chain terminator due to difficulty of EFdA- terminated viral DNA to translocate. Thus, EFdA is termed a nucleotide reverse transcriptase translocation inhibitor (NRTTI). However, the inhibition mechanism of EFdA in HIV-infected cells (primary or cell lines) remains unknown. Toward that end, Co-I Malim has established an innovative assay that enables study of the EFdA antiviral mechanism in HIV-infected cells. Additionally, in vitro passage experiments have identified mutations that impart EFdA resistance through two paradigm-shifting dual mechanisms or resistance: decreased incorporation/enhanced excision and decreased incorporation/enhanced translocation. Data on an EFdA analog suggest efficient inhibition of EFdA-resistant HIV, although the mechanism of this phenomenon is not understood. Notably, treatment with key new generation NNRTI doravirine (DOR) leads to resistance mutations that impart hypersusceptibility to EFdA, paving the way for EFdA/DOR combination therapies. We hypothesize that the structural attributes of EFdA and its analogs impact interactions with diverse RTs (wild-type, drug- resistant, from diverse clades, viruses), leading to clinically important differences in efficiency of inhibition, resistance, hypersusceptibility, and biochemical mechanism of action. This hypothesis will be tested through three specific aims, which endeavor to answer the above questions using a combination of novel sequencing, biochemical, structural, and virological approaches. This work will help optimize combination therapies that reduce drug burden and have exceptional long-acting potential, addressing adherence challenges of chronic HIV treatment.

项目总结