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Antimicrob Agents Chemother. 2017 Jun 27;61(7). pii: e02366-16. doi: 10.1128/AAC.02366-16. Print 2017 Jul.

Identification and Optimization of Thienopyridine Carboxamides as Inhibitors of HIV Regulatory Complexes.

Author information

1
Advanced Genetic Systems, San Francisco, California, USA.
2
Department of Biochemistry and Biophysics, University of California, San Francisco, California, USA.
3
Small Molecule Discovery Center and Department of Pharmaceutical Chemistry, University of California, San Francisco, California, USA.
4
School of Medicine, Tsinghua University, Beijing, China.
5
Small Molecule Discovery Center and Department of Pharmaceutical Chemistry, University of California, San Francisco, California, USA adam.renslo@ucsf.edu.

Abstract

Viral regulatory complexes perform critical functions during virus replication and are important targets for therapeutic intervention. In HIV, the Tat and Rev proteins form complexes with multiple viral and cellular factors to direct transcription and export of the viral RNA. These complexes are composed of many proteins and are dynamic, making them difficult to fully recapitulate in vitro Therefore, we developed a cell-based reporter assay to monitor the assembly of viral complexes for inhibitor screening. We screened a small-molecule library and identified multiple hits that inhibit the activity of the viral complexes. A subsequent chemistry effort was focused on a thieno[2,3-b]pyridine scaffold, examples of which inhibited HIV replication and the emergence from viral latency. Notable aspects of the effort to determine the structure-activity relationship (SAR) include migration to the regioisomeric thieno[2,3-c]pyridine ring system and the identification of analogs with single-digit nanomolar activity in both reporter and HIV infectivity assays, an improvement of >100-fold in potency over the original hits. These results validate the screening strategy employed and reveal a promising lead series for the development of a new class of HIV therapeutics.

KEYWORDS:

HIV; RNA; Rev; antivirals

PMID:
28416550
PMCID:
PMC5487668
DOI:
10.1128/AAC.02366-16
[Indexed for MEDLINE]
Free PMC Article

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