Journal article
Discovery and Mechanistic Investigation of Piperazinone Phenylalanine Derivatives with Terminal Indole or Benzene Ring as Novel HIV-1 Capsid Modulators
Molecules (Basel, Switzerland), v 27(23), p8415
01 Dec 2022
PMID: 36500508
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
HIV-1 capsid (CA) performs multiple roles in the viral life cycle and is a promising target for antiviral development. In this work, we describe the design, synthesis, assessment of antiviral activity, and mechanistic investigation of 20 piperazinone phenylalanine derivatives with a terminal indole or benzene ring. Among them,
exhibited moderate anti-HIV-1 activity with an EC
value of 5.89 μM, which was slightly weaker than the lead compound
(EC
= 0.75 μM). Interestingly, several compounds showed a preference for HIV-2 inhibitory activity, represented by
with an HIV-2 EC
value of 4.52 μM and nearly 5-fold increased potency over anti-HIV-1 (EC
= 21.81 μM), equivalent to
(EC
= 4.16 μM). Furthermore,
preferred to bind to the CA hexamer rather than to the monomer, similar to
, according to surface plasmon resonance results. Molecular dynamics simulation indicated that
and
bound at the same site. Additionally, we computationally analyzed the ADMET properties for
and
. Based on this analysis,
and
were predicted to have improved drug-like properties and metabolic stability over
, and no toxicities were predicted based on the chemotype of
and
. Finally, the experimental metabolic stability results of
in human liver microsomes and human plasma moderately correlated with our computational prediction. Our findings show that
is a promising small molecule targeting the HIV-1 CA protein with considerable development potential.
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Details
- Title
- Discovery and Mechanistic Investigation of Piperazinone Phenylalanine Derivatives with Terminal Indole or Benzene Ring as Novel HIV-1 Capsid Modulators
- Creators
- Shujing Xu - Shandong UniversityLin Sun - Shandong UniversityWaleed A Zalloum - American University of MadabaTianguang Huang - Shandong UniversityXujie Zhang - Shandong UniversityDang Ding - Shandong UniversityXiaoyu Shao - Shandong UniversityXiangyi Jiang - Shandong UniversityFabao Zhao - Shandong UniversitySimon Cocklin - Specifica (United States)Erik De Clercq - Rega Institute for Medical ResearchChristophe Pannecouque - Rega Institute for Medical ResearchAlexej Dick - Drexel UniversityXinyong Liu - Shandong UniversityPeng Zhan - Shandong University
- Publication Details
- Molecules (Basel, Switzerland), v 27(23), p8415
- Publisher
- MDPI
- Grant note
- R01 AI150491 / NIAID NIH HHS
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology
- Web of Science ID
- WOS:000897525200001
- Scopus ID
- 2-s2.0-85143696015
- Other Identifier
- 991021229882204721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology
- Chemistry, Multidisciplinary