Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Chemistry, Medicinal, Pharmacology & Pharmacy, antiviral agents, DDX3, helicase, HIV-1, host cofactors, inhibitors, BOX RNA HELICASE, REPLICATION, NUCLEOSIDE, ANALOGS, INFECTION, KNOCKDOWN, Anti-HIV Agents, Cell Line, Tumor, Computer Simulation, DEAD-box RNA Helicases, Drug Design, Drug Evaluation, Preclinical, Drug Screening Assays, Antitumor, Enzyme Inhibitors, Gene Knockdown Techniques, Humans, MicroRNAs, Rhodanine, Structure-Activity Relationship, Triazines, Virus Replication, 0304 Medicinal and Biomolecular Chemistry, 0305 Organic Chemistry, 1115 Pharmacology and Pharmaceutical Sciences, Medicinal & Biomolecular Chemistry, 3404 Medicinal and biomolecular chemistry, 3405 Organic chemistry

Abstract:

A hit optimization protocol applied to the first nonnucleoside inhibitor of the ATPase activity of human DEAD-box RNA helicase DDX3 led to the design and synthesis of second-generation rhodanine derivatives with better inhibitory activity toward cellular DDX3 and HIV-1 replication. Additional DDX3 inhibitors were identified among triazine compounds. Biological data were rationalized in terms of structure-activity relationships and docking simulations. Antiviral activity and cytotoxicity of selected DDX3 inhibitors are reported and discussed. A thorough analysis confirmed human DDX3 as a valid anti-HIV target. The compounds described herein represent a significant advance in the pursuit of novel drugs that target HIV-1 host cofactors.