Design, Synthesis and Structure—Activity Relationships of Phenylalanine-Containing Peptidomimetics as Novel HIV-1 Capsid Binders Based on Ugi Four-Component Reaction
oleh: Xiangkai Ji, Jing Li, Prem Prakash Sharma, Xiangyi Jiang, Brijesh Rathi, Zhen Gao, Lide Hu, Dongwei Kang, Erik De Clercq, Simon Cocklin, Chuanfeng Liu, Christophe Pannecouque, Alexej Dick, Xinyong Liu, Peng Zhan
| Format: | Article |
|---|---|
| Diterbitkan: | MDPI AG 2022-09-01 |
Deskripsi
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 <b>PF-74</b> 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 <b>I-19</b> exhibited the best anti-HIV-1 activity (EC<sub>50</sub> = 2.53 ± 0.84 μM, CC<sub>50</sub> = 107.61 ± 27.43 μM). In addition, <b>I-14</b> displayed excellent HIV-2 inhibitory activity (EC<sub>50</sub> = 2.30 ± 0.11 μM, CC<sub>50</sub> > 189.32 μM) with relatively low cytotoxicity, being more potent than that of the approved drug nevirapine (EC<sub>50</sub> > 15.02 μM, CC<sub>50</sub> > 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 <b>I-19</b> to HIV-1 CA. In summary, we further explored the structure—activity relationships (SARs) and selectivity of anti-HIV-1/HIV-2 of <b>PF-74</b> derivatives, which is conducive to discovering efficient anti-HIV drugs.