{"doi":"10.3390/v15051185","title":"Piperidine CD4-Mimetic Compounds Expose Vulnerable Env Epitopes Sensitizing HIV-1-Infected Cells to ADCC","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.","journal":"Viruses","year":2023,"id":357839,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":12,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9434,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":335146,"name":"William D. Tolbert","orcid":"0000-0001-7549-9596","position":1,"is_corresponding":false},{"id":1107999,"name":"Huile Zhu","orcid":null,"position":2,"is_corresponding":false},{"id":755013,"name":"Daniel Lee","orcid":"0000-0002-7322-1512","position":3,"is_corresponding":false},{"id":807709,"name":"Lorie Marchitto","orcid":"0000-0002-4367-0229","position":4,"is_corresponding":false},{"id":1107615,"name":"Tyler F. Higgins","orcid":"0000-0002-6624-2702","position":5,"is_corresponding":false},{"id":322035,"name":"Xuchen Zhao","orcid":null,"position":6,"is_corresponding":false},{"id":443635,"name":"Dung N. Nguyen","orcid":"0009-0006-7168-3234","position":7,"is_corresponding":false},{"id":350326,"name":"Rebekah Sherburn","orcid":"0000-0002-1683-3977","position":8,"is_corresponding":false},{"id":241566,"name":"Jonathan Richard","orcid":"0000-0002-9015-9589","position":9,"is_corresponding":false},{"id":241575,"name":"Gabrielle Gendron‐Lepage","orcid":"0000-0002-2671-3872","position":10,"is_corresponding":false},{"id":243836,"name":"Halima Medjahed","orcid":null,"position":11,"is_corresponding":false},{"id":357548,"name":"Mohammadjavad Mohammadi","orcid":null,"position":12,"is_corresponding":false},{"id":350336,"name":"Cameron F. Abrams","orcid":"0000-0002-1240-0816","position":13,"is_corresponding":false},{"id":335148,"name":"Marzena Pazgier","orcid":"0000-0003-0594-5057","position":14,"is_corresponding":false},{"id":350337,"name":"Amos B. Smith","orcid":"0000-0002-1712-8567","position":15,"is_corresponding":false},{"id":241588,"name":"Andrés Finzi","orcid":"0000-0002-4992-5288","position":16,"is_corresponding":false},{"id":241572,"name":"Shilei Ding","orcid":"0000-0003-1895-5131","position":0,"is_corresponding":true}],"reference_count":43,"raw_metadata":null,"created_at":"2026-07-19T01:13:39.186262Z","pmid":"37243271","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}