Structural and mechanistic bases for a potent HIV-1 capsid inhibitor-Reference-Cited by-同舟云学术

Structural and mechanistic bases for a potent HIV-1 capsid inhibitor

Published:2020-10-15 Issue:6514 Volume:370 Page:360-364
ISSN:0036-8075
Container-title:Science
language:en
Short-container-title:Science

Author:

Bester Stephanie M.¹^ORCID,Wei Guochao¹^ORCID,Zhao Haiyan²^ORCID,Adu-Ampratwum Daniel³^ORCID,Iqbal Naseer²^ORCID,Courouble Valentine V.⁴^ORCID,Francis Ashwanth C.⁵,Annamalai Arun S.¹^ORCID,Singh Parmit K.⁶⁷^ORCID,Shkriabai Nikoloz¹,Van Blerkom Peter²^ORCID,Morrison James¹^ORCID,Poeschla Eric M.¹^ORCID,Engelman Alan N.⁶⁷^ORCID,Melikyan Gregory B.⁵^ORCID,Griffin Patrick R.⁴^ORCID,Fuchs James R.³^ORCID,Asturias Francisco J.²^ORCID,Kvaratskhelia Mamuka¹^ORCID

Affiliation:

1. Division of Infectious Diseases, Anschutz Medical Campus, University of Colorado School of Medicine, Aurora, CO 80045, USA.

2. Department of Biochemistry and Molecular Genetics, Anschutz Medical Campus, University of Colorado School of Medicine, Aurora, CO 80045, USA.

3. Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA.

4. Department of Molecular Medicine, The Scripps Research Institute, Jupiter, FL 33458, USA.

5. Department of Pediatrics, Infectious Diseases, Emory University, Atlanta, GA 30322, USA.

6. Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.

7. Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.

Abstract

The potent HIV-1 capsid inhibitor GS-6207 is an investigational principal component of long-acting antiretroviral therapy. We found that GS-6207 inhibits HIV-1 by stabilizing and thereby preventing functional disassembly of the capsid shell in infected cells. X-ray crystallography, cryo–electron microscopy, and hydrogen-deuterium exchange experiments revealed that GS-6207 tightly binds two adjoining capsid subunits and promotes distal intra- and inter-hexamer interactions that stabilize the curved capsid lattice. In addition, GS-6207 interferes with capsid binding to the cellular HIV-1 cofactors Nup153 and CPSF6 that mediate viral nuclear import and direct integration into gene-rich regions of chromatin. These findings elucidate structural insights into the multimodal, potent antiviral activity of GS-6207 and provide a means for rationally developing second-generation therapies.

Funder

NIH Office of the Director

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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