{"doi":"10.1101/2023.01.02.522483","title":"Indoline CD4-mimetic Compounds Mediate Potent and Broad HIV-1 Inhibition and Sensitization to Antibody-dependent Cellular Cytotoxicity","abstract":"Abstract Binding to the host cell receptors, CD4 and CCR5/CXCR4, triggers large-scale conformational changes in the human immunodeficiency virus (HIV-1) envelope glycoprotein (Env) trimer [(gp120/gp41) 3 ] that promote virus entry into the cell. CD4-mimetic compounds (CD4mcs) comprise small organic molecules that bind in the highly conserved CD4-binding site of gp120 and prematurely induce inactivating Env conformational changes, including shedding of gp120 from the Env trimer. By inducing more “open,” antibody-susceptible Env conformations, CD4mcs also sensitize HIV-1 virions to neutralization by antibodies and infected cells to antibody-dependent cellular cytotoxicity (ADCC). Here, we report the design, synthesis and evaluation of novel CD4mcs based on an indoline scaffold. Compared with our current lead indane scaffold CD4mc, BNM-III-170, several indoline CD4mcs exhibit increased potency and breadth against HIV-1 variants from different geographic clades. Viruses that were selected for resistance to the lead indane CD4mc, BNM-III-170, are susceptible to inhibition by the indoline CD4mcs. The indoline CD4mcs also potently sensitize HIV-1-infected cells to ADCC mediated by plasma from HIV-1-infected individuals. Crystal structures indicate that the indoline CD4mcs gain potency compared to the indane CD4mcs through more favorable π-π overlap from the indoline pose and by making favorable contacts with the vestibule of the CD4-binding pocket on gp120. The rational design of indoline CD4mcs thus holds promise for further improvements in antiviral activity, potentially contributing to efforts to treat and prevent HIV-1 infection.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":402281,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9548,"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":280611,"name":"Saumya Anang","orcid":"0000-0001-7222-8934","position":1,"is_corresponding":false},{"id":1179982,"name":"Zhen Gong","orcid":"0000-0003-0760-1493","position":2,"is_corresponding":false},{"id":357548,"name":"Mohammadjavad Mohammadi","orcid":null,"position":3,"is_corresponding":false},{"id":241566,"name":"Jonathan Richard","orcid":"0000-0002-9015-9589","position":4,"is_corresponding":false},{"id":621586,"name":"Catherine Bourassa","orcid":"0000-0003-1805-8860","position":5,"is_corresponding":false},{"id":1180184,"name":"Kenny T. Severino","orcid":null,"position":6,"is_corresponding":false},{"id":1038328,"name":"Hannah Richter","orcid":"0009-0003-7120-2910","position":7,"is_corresponding":false},{"id":908031,"name":"Derek Yang","orcid":"0000-0001-8959-384X","position":8,"is_corresponding":false},{"id":677237,"name":"Hung-Ching Chen","orcid":"0000-0002-3359-5878","position":9,"is_corresponding":false},{"id":822652,"name":"Ta-Jung Chiu","orcid":"0000-0003-3816-8805","position":10,"is_corresponding":false},{"id":16991,"name":"Michael S. Seaman","orcid":"0000-0001-6444-3562","position":11,"is_corresponding":false},{"id":350327,"name":"Navid Madani","orcid":"0000-0002-6679-6078","position":12,"is_corresponding":false},{"id":350336,"name":"Cameron F. Abrams","orcid":"0000-0002-1240-0816","position":13,"is_corresponding":false},{"id":241588,"name":"Andrés Finzi","orcid":"0000-0002-4992-5288","position":14,"is_corresponding":false},{"id":51279,"name":"Wayne A. Hendrickson","orcid":"0000-0003-1412-5747","position":15,"is_corresponding":false},{"id":105634,"name":"Joseph Sodroski","orcid":"0000-0002-9750-1615","position":16,"is_corresponding":false},{"id":350337,"name":"Amos B. Smith","orcid":"0000-0002-1712-8567","position":17,"is_corresponding":false},{"id":1119846,"name":"Christopher Fritschi","orcid":"0000-0002-7724-8130","position":0,"is_corresponding":true}],"reference_count":56,"raw_metadata":null,"created_at":"2026-07-19T01:20:27.903246Z","pmid":null,"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":[]}