期刊
VIRUSES-BASEL
卷 15, 期 5, 页码 -出版社
MDPI
DOI: 10.3390/v15051185
关键词
HIV-1; small CD4 mimetic compounds (CD4mc); Phe43 cavity; envelope glycoproteins; neutralization; antibody-dependent cellular cytotoxicity (ADCC)
类别
The HIV-1 accessory proteins Nef and Vpu can decrease CD4 levels to protect infected cells from antibody-dependent cellular cytotoxicity (ADCC) and prevent exposure of vulnerable epitopes. Small-molecule CD4 mimetics (CD4mc) based on indane and piperidine scaffolds sensitize HIV-1-infected cells to ADCC by exposing CD4-induced (CD4i) epitopes. A new family of CD4mc derivatives based on the piperidine scaffold, targeting the conserved Asp(368) Env residue, showed improved activity against difficult-to-neutralize viruses and sensitized infected cells to ADCC. These molecules have potential as candidates for strategies aiming to eliminate HIV-1-infected cells.
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 Asp(368) 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 a-carboxylic acid group of Asp(368), 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.
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