Design, synthesis, and mechanism study of dimerized phenylalanine derivatives as novel HIV-1 capsid inhibitors

Zhang, Xujie; Sun, Lin; Meuser, Megan E.; Zalloum, Waleed A.; Xu, Shujing; Huang, Tianguang; Cherukupalli, Srinivasulu; Jiang, Xiangyi; Ding, Xiao; Tao, Yucen; Kang, Dongwei; Clercq, Erik De; Pannecouque, Christophe; Dick, Alexej; Simon, Chantal; Liu, Xinyong; Zhan, Peng

doi:10.1016/j.ejmech.2021.113848

Cited by 16 publications

(19 citation statements)

References 61 publications

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“…As mentioned above, PF‐74 could disturb the CA‐host factor interactions by acting on capsid proteins competitively with host factors, such as CPSF6 and nucleoporin 153. Therefore, compound d13 and d19 were selected for competitive CA hexamer binding assay with CPSF6 based on SPR technology 36 . As shown in Figure 3, d13 and d19 effectively inhibited the binding of CPSF6 to CA hexamer with IC 50 values of 92.4 and 33.4 nM, respectively, which are similar to PF‐74 (IC 50 = 26.6 nM).…”

Section: Resultsmentioning

confidence: 96%

“…Therefore, compound d13 and d19 were selected for competitive CA hexamer binding assay with CPSF6 based on SPR technology. 36 As shown in Figure 3, Abbreviation: HIV, human immunodeficiency virus. a EC 50 : concentration required to achieve 50% protection of MT-4 cell cultures against HIV-1 induced cytopathicity, as determined using the MTT method.…”

Section: Spr-based Competition Assay With Cpsf6mentioning

confidence: 99%

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Discovery of novel 1,2,4‐triazole phenylalanine derivatives targeting an unexplored region within the interprotomer pocket of the HIV capsid protein

Jiang

Sharma

Rathi

et al. 2022

Journal of Medical Virology

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Human immunodeficiency virus (HIV) capsid (CA) protein is a promising target for developing novel anti‐HIV drugs. Starting from highly anticipated CA inhibitors PF‐74, we used scaffold hopping strategy to design a series of novel 1,2,4‐triazole phenylalanine derivatives by targeting an unexplored region composed of residues 106–109 in HIV‐1 CA hexamer. Compound d19 displayed excellent antiretroviral potency against HIV‐1 and HIV‐2 strains with EC50 values of 0.59 and 2.69 µM, respectively. Additionally, we show via surface plasmon resonance (SPR) spectrometry that d19 preferentially interacts with the hexameric form of CA, with a significantly improved hexamer/monomer specificity ratio (ratio = 59) than PF‐74 (ratio = 21). Moreover, we show via SPR that d19 competes with CPSF‐6 for binding to CA hexamers with IC50 value of 33.4 nM. Like PF‐74, d19 inhibits the replication of HIV‐1 NL4.3 pseudo typed virus in both early and late stages. In addition, molecular docking and molecular dynamics simulations provide binding mode information of d19 to HIV‐1 CA and rationale for improved affinity and potency over PF‐74. Overall, the lead compound d19 displays a distinct chemotype form PF‐74, improved CA affinity, and anti‐HIV potency.

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Section: Resultsmentioning

confidence: 96%

Section: Spr-based Competition Assay With Cpsf6mentioning

confidence: 99%

Discovery of novel 1,2,4‐triazole phenylalanine derivatives targeting an unexplored region within the interprotomer pocket of the HIV capsid protein

Jiang

Sharma

Rathi

et al. 2022

Journal of Medical Virology

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“…Another series of phenylalanine derivatives covalently cross-linked into dimers by using 2-piperazineone or 2,5-piperazinedione was shown to possess higher activities than phenylalanine-derived monomers. Although the most potent inhibitor in this series, Q-c4 (Table 1), showed slightly lower binding affinity to HIV-1 CA than the control molecule PF74, its antiviral activity was comparable with PF74 [70]. It exhibited an EC50 value of 0.57 µM in the infected MT-4 human T-cell line.…”

Section: Phenylalanine Derivatives 11l and Q-c4mentioning

confidence: 90%

“…Q-c4 binds to the same capsid interprotomer pocket as PF74 and thereby prevents binding of HIV-1 CA with the cellular factors CPSF6 and NUP153. It affects the HIV-1 life cycle both at early and late stages, dominating in the late stage of the viral life cycle [70].…”

Section: Phenylalanine Derivatives 11l and Q-c4mentioning

confidence: 99%

Targeting the Virus Capsid as a Tool to Fight RNA Viruses

Hozáková

Vokatá

Ruml

et al. 2022

Viruses

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Several strategies have been developed to fight viral infections, not only in humans but also in animals and plants. Some of them are based on the development of efficient vaccines, to target the virus by developed antibodies, others focus on finding antiviral compounds with activities that inhibit selected virus replication steps. Currently, there is an increasing number of antiviral drugs on the market; however, some have unpleasant side effects, are toxic to cells, or the viruses quickly develop resistance to them. As the current situation shows, the combination of multiple antiviral strategies or the combination of the use of various compounds within one strategy is very important. The most desirable are combinations of drugs that inhibit different steps in the virus life cycle. This is an important issue especially for RNA viruses, which replicate their genomes using error-prone RNA polymerases and rapidly develop mutants resistant to applied antiviral compounds. Here, we focus on compounds targeting viral structural capsid proteins, thereby inhibiting virus assembly or disassembly, virus binding to cellular receptors, or acting by inhibiting other virus replication mechanisms. This review is an update of existing papers on a similar topic, by focusing on the most recent advances in the rapidly evolving research of compounds targeting capsid proteins of RNA viruses.

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“…20,21 With so much importance now placed on the synthesis of small molecules with a diverse 3-dimensional structure, Stockman had provided a versatile synthetic route, with 6a containing four of the five chiral centres found in pinnaic acid. [22][23][24][25] The drawback however, was that the carbon α to the isoxazolidine nitrogen exhibited the wrong relative stereochemistry compared with the natural product (PA). Attempts at epimerisation by Stockman were only successful upon reductive cleavage of the N-O bond.…”

Section: Introductionmentioning

confidence: 99%

Chemical synthesis of a library of natural product-like derivatives based on pinnaic acid and initial evaluation of their anti-cancer activity

et al. 2022

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Design, synthesis, and mechanism study of dimerized phenylalanine derivatives as novel HIV-1 capsid inhibitors

Cited by 16 publications

References 61 publications

Discovery of novel 1,2,4‐triazole phenylalanine derivatives targeting an unexplored region within the interprotomer pocket of the HIV capsid protein

Discovery of novel 1,2,4‐triazole phenylalanine derivatives targeting an unexplored region within the interprotomer pocket of the HIV capsid protein

Targeting the Virus Capsid as a Tool to Fight RNA Viruses

Chemical synthesis of a library of natural product-like derivatives based on pinnaic acid and initial evaluation of their anti-cancer activity

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