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Structural and Chemical Analysis of Highly Potent ALLINI Platform

高效 ALLINI 平台的结构和化学分析

基本信息

批准号：
9789826
负责人：
Baek Kim
金额：
$ 38.98万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-24 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9789826
关键词：
Animals Anti-HIV Agents Antiviral Agents Binding Biochemical Canis familiaris Capsid Catalytic Domain Cells Chemicals Clinical Drug Kinetics Evaluation Follow-Up Studies Genetic Enhancement Genome Goals HIV HIV-1 HIV-1 integrase Health Human In Vitro Individual Integrase Integrase Inhibitors Investigation Libraries Life Cycle Stages Mutation Pathogenesis Patients Peripheral Blood Mononuclear Cell Pharmaceutical Chemistry Proteins Rattus Reporting Research Institute Resistance Roentgen Rays Safety Series Site Structure Therapeutic Agents Therapeutic Index Time Toxic effect Viral Viral Proteins Virus Work X-Ray Crystallography animal safety anti-viral efficacy base clinical application computational chemistry design dimer drug discovery genetic approach innovation lens epithelium-derived growth factor monomer novel operation particle pre-clinical research clinical testing resistance mutation scaffold screening structural biology targeted agent tissue culture transcriptional coactivator p75 viral RNA virology

项目摘要

Project Summary – Kim While current anti-HIV therapeutic agents contribute to the effective suppression of HIV-1 in patients, actual choices for long-term treatment is rather limited due to viral escape, cross-resistance, and toxicity, demanding discovery of newer and safer classes of anti-HIV agents. HIV-1 requires various host intracellular factors for completing its life cycle and pathogenesis. Targeting the interactions between viral proteins and these host intracellular factors has been extensively explored as a potential anti-viral discovery path while anti-HIV agents targeting the viral interactions with intracellular factors are currently limited. A recent collaborative work between Emory Center for Drug Discovery (CDD) and ST Pharm, CO, LTD identified a highly potent anti-HIV compound with outstanding in vitro and animal toxicity and pharmacokinetics, STP03-0404: STP03-0404 was originally identified as an anti-HIV hit by the random anti- HIV compound screening operation of ST Pharm that employed a series of chemical scaffold libraries uniquely developed by ST Pharm. The EC50 values of STP03-0404 determined by Southern Research Institute (SRI, Frederick, MD) with human PBMCs and various clinical HIV-1 isolates, and also independently determined by Emory CDD are in pico-molar ranges. Furthermore, the tissue culture based therapeutic index of STP03-0404 was 40,000-1,000,000, and the preclinical animal investigations with rats and dogs demonstrated its outstanding safety and excellent pharmacokinetics. Excitingly, our extensive computational structure-based search efforts and initial X-ray crystallographic analysis proposed that STP03-0404 targets the LEDGF/p75 binding pocket at the interface between two monomers of HIV-1 integrase (IN) and therefore this compound works as an allosteric integrase inhibitor (ALLINI). Importantly, we found that STP03-0404 displays up to ~ 1,000 times more effective anti-HIV-1 activity than previously reported ALLINIs. Furthermore, STP03-0404 effectively inhibits clinical HIV-1 strains with resistance to catalytic site integrase inhibitors such as Raltegravir. Therefore, in this application, we will structurally and chemically investigate STP03-0404 as a highly potent and safe ALLINI platform. For these investigations, we propose to employ a series of in-depth biochemical, structural biology, virological/genetic approaches as well as medicinal chemistry/chemical optimization designed for new derivatives of STP03-0404 with enhanced genetic barrier to resistance. Ultimate goal of this application is to meet the current demand for newer and safer anti-HIV agents by pre-clinically investigating STP03-0404 as a novel, potent and safe anti-HIV drug discovery platform.

项目摘要- Kim