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Journal article
Design, Synthesis and Structure—Activity Relationships of Phenylalanine-Containing Peptidomimetics as Novel HIV-1 Capsid Binders Based on Ugi Four-Component Reaction
Molecules (Basel, Switzerland), v 27(18), p5995
01 Jan 2022
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
As a key structural protein, HIV capsid (CA) protein plays multiple roles in the HIV life cycle, and is considered a promising target for anti-HIV treatment. Based on the structural information of CA modulator PF-74 bound to HIV-1 CA hexamer, 18 novel phenylalanine derivatives were synthesized via the Ugi four-component reaction. In vitro anti-HIV activity assays showed that most compounds exhibited low-micromolar-inhibitory potency against HIV. Among them, compound I-19 exhibited the best anti-HIV-1 activity (EC50 = 2.53 ± 0.84 μM, CC50 = 107.61 ± 27.43 μM). In addition, I-14 displayed excellent HIV-2 inhibitory activity (EC50 = 2.30 ± 0.11 μM, CC50 > 189.32 μM) with relatively low cytotoxicity, being more potent than that of the approved drug nevirapine (EC50 > 15.02 μM, CC50 > 15.2 μM). Additionally, surface plasmon resonance (SPR) binding assays demonstrated direct binding to the HIV CA protein. Moreover, molecular docking and molecular dynamics simulations provided additional information on the binding mode of I-19 to HIV-1 CA. In summary, we further explored the structure—activity relationships (SARs) and selectivity of anti-HIV-1/HIV-2 of PF-74 derivatives, which is conducive to discovering efficient anti-HIV drugs.
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Details
- Title
- Design, Synthesis and Structure—Activity Relationships of Phenylalanine-Containing Peptidomimetics as Novel HIV-1 Capsid Binders Based on Ugi Four-Component Reaction
- Creators
- Xiangkai Ji - Shandong UniversityJing LiPrem SharmaXiangyi JiangBrijesh RathiZhen GaoLide HuDongwei KangErik De ClercqSimon CocklinChuanfeng LiuChristophe PannecouqueAlexej DickJingjing Li - Urban Health Collaborative (2015-)Xinyong LiuPeng Zhan
- Publication Details
- Molecules (Basel, Switzerland), v 27(18), p5995
- Publisher
- MDPI AG
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology; Urban Health Collaborative
- Web of Science ID
- WOS:000857716700001
- Scopus ID
- 2-s2.0-85138325738
- Other Identifier
- 991019173531304721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology
- Chemistry, Multidisciplinary