A Broad-Spectrum Antiviral Molecule, Protoporphyrin IX, Acts as a Moderator of HIV-1 Capsid Assembly by Targeting the Capsid Hexamer

Da-Wei Zhang; Liangxu Xie; Xiao-Shuang Xu; Yimin Li; Xiaojun Xu

doi:10.1128/spectrum.02663-22

Microbiology Spectrum (Feb 2023)

A Broad-Spectrum Antiviral Molecule, Protoporphyrin IX, Acts as a Moderator of HIV-1 Capsid Assembly by Targeting the Capsid Hexamer

Da-Wei Zhang,
Liangxu Xie,
Xiao-Shuang Xu,
Yimin Li,
Xiaojun Xu

Affiliations

Da-Wei Zhang: Institute of Bioinformatics and Medical Engineering, School of Electrical and Information Engineering, Jiangsu University of Technology, Changzhou, China
Liangxu Xie: Institute of Bioinformatics and Medical Engineering, School of Electrical and Information Engineering, Jiangsu University of Technology, Changzhou, China
Xiao-Shuang Xu: Institute of Bioinformatics and Medical Engineering, School of Electrical and Information Engineering, Jiangsu University of Technology, Changzhou, China
Yimin Li: College of Pharmacy and Key Laboratory for Research and Development of “Qin Medicine” of Shaanxi Administration of Chinese Medicine, Shaanxi University of Chinese Medicine, Xixian New District, China
Xiaojun Xu: Institute of Bioinformatics and Medical Engineering, School of Electrical and Information Engineering, Jiangsu University of Technology, Changzhou, China

DOI: https://doi.org/10.1128/spectrum.02663-22
Journal volume & issue: Vol. 11, no. 1

Abstract

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ABSTRACT The capsid protein (CA), an essential component of human immunodeficiency virus type 1 (HIV-1), represents an appealing target for antivirals. Small molecules targeting the CAI-binding cavity in the C-terminal domain of HIV-1 CA (CA CTD) confer potent antiviral activities. In this study, we report that a small molecule, protoporphyrin IX (PPIX), targets the HIV-1 CA by binding to this pocket. PPIX was identified via in vitro drug screening, using a homogeneous and time-resolved fluorescence-based assay. CA multimerization and a biolayer interferometry (BLI) assay showed that PPIX promoted CA multimerization and bound directly to CA. The binding model of PPIX to CA CTD revealed that PPIX forms hydrogen bonds with the L211and E212 residues in the CA CTD. Moreover, the BLI assay demonstrated that this compound preferentially binds to the CA hexamer versus the monomer. The superposition of the CAI CTD-PPIX complex and the hexameric CA structure suggests that PPIX binds to the interface formed by the NTD and the CTD between adjacent protomers in the CA hexamer via the T72 and E212 residues, serving as a glue to enhance the multimerization of CA. Taken together, our studies demonstrate that PPIX, a hexamer-targeted CA assembly enhancer, should be a new chemical probe for the discovery of modulators of the HIV-1 capsid assembly. IMPORTANCE CA and its assembled viral core play essential roles in distinct steps during HIV-1 replication, including reverse transcription, integration, nuclear entry, virus assembly, and maturation through CA–CA or CA–host factor interactions. These functions of CA are fundamental for HIV-1 pathogenesis, making it an appealing target for antiviral therapy. In the present study, we identified protoporphyrin IX (PPIX) as a candidate CA modulator that can promote CA assembly and prefers binding the CA hexamer versus the monomer. PPIX, like a glue, bound at the interfaces between CA subunits to accelerate CA multimerization. Therefore, PPIX could be used as a new lead for a CA modulator, and it holds potential research applications.

Published in Microbiology Spectrum

ISSN: 2165-0497 (Online)
Publisher: American Society for Microbiology
Country of publisher: United States
LCC subjects: Science: Microbiology
Website: https://journals.asm.org/journal/spectrum

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