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Piperidine CD4-Mimetic Compounds Expose Vulnerable Env Epitopes Sensitizing HIV-1-Infected Cells to ADCC.

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Ding S, Tolbert WD, Zhu H, Lee D, Marchitto L, Higgins T, Zhao X, Nguyen D, Sherburn R, Richard J, Gendron-Lepage G, Medjahed H, Mohammadi M, Abrams C, Pazgier M, Smith AB, Finzi A
OpenAccess logo Viruses 15 (2023)
Related entries: 8gcz, 8gd1, 8gd3, 8gd5, 8gjt

Cited: 7 times
EuropePMC logo PMID: 37243271

Abstract

The ability of the HIV-1 accessory proteins Nef and Vpu to decrease CD4 levels contributes to the protection of infected cells from antibody-dependent cellular cytotoxicity (ADCC) by preventing the exposure of Env vulnerable epitopes. Small-molecule CD4 mimetics (CD4mc) based on the indane and piperidine scaffolds such as (+)-BNM-III-170 and (S)-MCG-IV-210 sensitize HIV-1-infected cells to ADCC by exposing CD4-induced (CD4i) epitopes recognized by non-neutralizing antibodies that are abundantly present in plasma from people living with HIV. Here, we characterize a new family of CD4mc, (S)-MCG-IV-210 derivatives, based on the piperidine scaffold which engages the gp120 within the Phe43 cavity by targeting the highly conserved Asp368 Env residue. We utilized structure-based approaches and developed a series of piperidine analogs with improved activity to inhibit the infection of difficult-to-neutralize tier-2 viruses and sensitize infected cells to ADCC mediated by HIV+ plasma. Moreover, the new analogs formed an H-bond with the α-carboxylic acid group of Asp368, opening a new avenue to enlarge the breadth of this family of anti-Env small molecules. Overall, the new structural and biological attributes of these molecules make them good candidates for strategies aimed at the elimination of HIV-1-infected cells.

Articles - 8gd0 mentioned but not cited (4)

  1. Piperidine CD4-Mimetic Compounds Expose Vulnerable Env Epitopes Sensitizing HIV-1-Infected Cells to ADCC. Ding S, Tolbert WD, Zhu H, Lee D, Marchitto L, Higgins T, Zhao X, Nguyen D, Sherburn R, Richard J, Gendron-Lepage G, Medjahed H, Mohammadi M, Abrams C, Pazgier M, Smith AB, Finzi A. Viruses 15 1185 (2023)
  2. Characterization of 3D interconnected microstructural network in mixed ionic and electronic conducting ceramic composites. Harris WM, Brinkman KS, Lin Y, Lin Y, Su D, Cocco AP, Nakajo A, DeGostin MB, Chen-Wiegart YC, Wang J, Chen F, Chu YS, Chiu WK. Nanoscale 6 4480-4485 (2014)
  3. Promising solid electrolyte material for an IT-SOFC: crystal structure of the cerium gadolinium holmium oxide Ce0.8Gd0.1Ho0.1O1.9 between 295 and 1023 K. Rahayu S, Forrester JS, Kale GM, Ghadiri M. Acta Crystallogr C Struct Chem 74 236-239 (2018)
  4. research-article Piperidine CD4-mimetic compounds expose vulnerable Env epitopes sensitizing HIV-1-infected cells to ADCC. Ding S, Tolbert WD, Zhu H, Lee D, Higgins T, Zhao X, Nguyen D, Sherburn R, Richard J, Lepage GG, Medjahed H, Mohammadi M, Abrams C, Pazgier M, Smith AB, Finzi A. bioRxiv 2023.03.23.533923 (2023)


Articles citing this publication (3)

  1. Soluble CD4 and low molecular weight CD4-mimetic compounds sensitize cells to be killed by anti-HIV cytotoxic immunoconjugates. Pincus SH, Stackhouse M, Watt C, Ober K, Cole FM, Chen HC, Smith Iii AB, Peters T. J Virol e0115423 (2023)
  2. Structure-function analyses reveal key molecular determinants of HIV-1 CRF01_AE resistance to the entry inhibitor temsavir. Prévost J, Chen Y, Zhou F, Tolbert WD, Gasser R, Medjahed H, Nayrac M, Nguyen DN, Gottumukkala S, Hessell AJ, Rao VB, Pozharski E, Huang RK, Matthies D, Finzi A, Pazgier M. Nat Commun 14 6710 (2023)
  3. V3 tip determinants of susceptibility to inhibition by CD4-mimetic compounds in natural clade A human immunodeficiency virus (HIV-1) envelope glycoproteins. Anang S, Zhang S, Fritschi C, Chiu T-J, Yang D, Smith Iii AB, Madani N, Sodroski J. J Virol 97 e0117123 (2023)


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