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From design to biological mechanism evaluation of phenylalanine-bearing HIV-1 capsid inhibitors targeting a vital assembly interface
Journal article   Peer reviewed

From design to biological mechanism evaluation of phenylalanine-bearing HIV-1 capsid inhibitors targeting a vital assembly interface

Shujing Xu, Lin Sun, Waleed A. Zalloum, Xujie Zhang, Tianguang Huang, Dang Ding, Yucen Tao, Fabao Zhao, Shenghua Gao, Dongwei Kang, …
Chinese chemical letters, v 34(3), 107611
Mar 2023
DOI: https://doi.org/10.1016/j.cclet.2022.06.034
Featured in Collection :   UN Sustainable Development Goals @ Drexel

Abstract

Assembly Capsid inhibitor Drug design HIV-1 NTD-CTD interface
HIV-1 capsid protein (CA) has emerged as a promising target for antiviral treatment considering its structural and regulatory roles in HIV-1 replication. Here, we disclose the design, synthesis, biological assessment, and mechanism investigation of a novel series of phenylalanine derivatives gained by further structural modification of PF74. The newly synthesized compounds demonstrated potent anti-HIV activity, represented by 7n displayed anti-HIV-1 activity 6.25-fold better than PF74, and 7h showed anti-HIV-2 activity with nearly 139 times improved efficacy over PF74. Surface plasmon resonance (SPR) studies of representative compounds proved that HIV-1 CA was the binding target. Competitive SPR studies using CPSF6 and NUP153 peptides identified that 7n binds to a vital CA assembly interface between the N-terminal and C-terminal domain (NTD-CTD interface). Action stage determination assay revealed that the newly synthesized compounds were antiviral with a dual-stage inhibitory profile. Molecular dynamics (MD) simulations offered the crucial foundation for the hopeful antiviral potency of 7n. Besides, 7m and 7n modestly increased metabolic stabilities in human liver microsome (HLM) and human plasma compared to PF74. Overall, these studies offer valuable insights and can regard as the beginning for succedent medicinal chemistry endeavors to discover promising HIV capsid inhibitors with improved efficacy and better drug-like characteristics. Taking PF74 as a lead compound, a structure-based drug design strategy was employed to design moderators of the capsid NTD-CTD interface, which led to the identification of new and potent phenylalanine derivatives. Among them, 7n exhibited anti-HIV-1 activity 6.25-fold better than PF74, and 7h showed anti-HIV-2 activity with almost 139 times increased potency over PF74. [Display omitted]

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Collaboration types
Domestic collaboration
International collaboration
Web of Science research areas
Chemistry, Multidisciplinary
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