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  • Title: Design, Synthesis and Structure-Activity Relationships of Phenylalanine-Containing Peptidomimetics as Novel HIV-1 Capsid Binders Based on Ugi Four-Component Reaction.
    Author: Ji X, Li J, Sharma PP, Jiang X, Rathi B, Gao Z, Hu L, Kang D, De Clercq E, Cocklin S, Liu C, Pannecouque C, Dick A, Liu X, Zhan P.
    Journal: Molecules; 2022 Sep 14; 27(18):. PubMed ID: 36144727.
    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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