Preclinical Development of HIV Vif Antagonists

摘要 这项修订的申请是根据PA-17-302规定的第一阶段SBIR赠款，其中NIAID和 DAIDS曾表示特别强调“针对艾滋病病毒药物的开发” 用于治疗艾滋病毒感染的新的病毒或细胞靶点。我们建议的目标是 通过对一项首例临床研究进行临床前研究，满足评估新药靶点的呼吁 抗逆转录病毒(ARV)类疗法，我们已为其奠定了坚实的基础 通过先导开发HIV-1(HIV)Vif拮抗剂的作用机制(MOA)。这个 这里描述的化合物使宿主细胞因子APOBEC3G(A3G)和APOBEC3F (A3F)参与先天免疫，通过APOBEC依赖广泛中和艾滋病毒 反转录过程中病毒基因组的高度突变。我们已经进行了药物治疗 化学优化铅，提高对个位数纳摩尔范围内的有效性 从A、B和C分支分离出的艾滋病毒自本提案最初提交以来，我们也有 包括前药战略，以增加体内血浆半衰期和化学合成 领头羊SN38-L和前药伊利诺-L都进行了优化。此外，ADMET研究 揭示了有希望的参数，并解决了最初审查者对毒性的担忧。 根据审查者的建议，这份SBIR提案现在寻求将详细的 药代动力学(PK)研究、人源化小鼠体内疗效研究和病毒耐药性研究 学习。根据审查员的要求，FDA根据《指南》要求进行的研究 行业抗病毒产品开发：进行病毒学研究并向 该机构已被移至第二阶段。

SUMMARY 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.