Chemical profiling of HIV-1 capsid-targeting antiviral PF74

• Authors: Lei Wang, University of Minnesota, Minneapolis; Mary C Casey, University of Missouri School of Medicine; Sanjeev Kumar V Vernekar, University of Minnesota, Minneapolis; Ha T Do, University of Minnesota, Minneapolis; Rajkumar Lalji Sahani, University of Minnesota, Minneapolis; Karen Kirby, Emory University; Haijuan Du, Emory University; Atsuko Hachiya, National Hospital Organization; Huanchun Zhang, Emory University; Philip Tedbury, Emory University; Jiashu Xie, University of Minnesota, Minneapolis; Stefan Sarafianos, Emory University; Zhengqiang Wang, University of Minnesota, Minneapolis
• Journal Title: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
• Volume: Volume 200
• Publisher: ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER | 2020-08-15, Pages 112427-112427
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1016/j.ejmech.2020.112427
• Subjects: Health Sciences, Pharmacology; Engineering, Chemical
• Keywords: Science & Technology; Life Sciences & Biomedicine; Chemistry, Medicinal; Pharmacology & Pharmacy; HIV-1; Capsid-targeting antivirals; PF74; THERMAL SHIFT ASSAYS; CYCLOPHILIN-A; REPLICATION; INFECTION; PROTEIN; ROLES; INHIBITION; DISCOVERY; POTENT; CELLS

Abstract

The capsid protein (CA) of HIV-1 plays essential roles in multiple steps of the viral replication cycle by assembling into functional capsid core, controlling the kinetics of uncoating and nuclear entry, and interacting with various host factors. Targeting CA represents an attractive yet underexplored antiviral approach. Of all known CA-targeting small molecule chemotypes, the peptidomimetic PF74 is particularly interesting because it binds to the same pocket used by a few important host factors, resulting in highly desirable antiviral phenotypes. However, further development of PF74 entails understanding its pharmacophore and mitigating its poor metabolic stability. We report herein the design, synthesis, and evaluation of a large number of PF74 analogs aiming to provide a comprehensive chemical profiling of PF74 and advance the understanding on its detailed binding mechanism and pharmacophore. The analogs, containing structural variations mainly in the aniline domain and/or the indole domain, were assayed for their effect on stability of CA hexamers, antiviral activity, and cytotoxicity. Selected analogs were also tested for metabolic stability in liver microsomes, alone or in the presence of a CYP3A inhibitor. Collectively, our studies identified important pharmacophore elements and revealed additional binding features of PF74, which could aid in future design of improved ligands to better probe the molecular basis of CA-host factor interactions, design strategies to disrupt them, and ultimately identify viable CA-targeting antiviral leads.