{"doi":"10.1371/journal.ppat.1009671","title":"A highly potent and safe pyrrolopyridine-based allosteric HIV-1 integrase inhibitor targeting host LEDGF/p75-integrase interaction site","abstract":"Allosteric integrase inhibitors (ALLINIs) are a class of experimental anti-HIV agents that target the noncatalytic sites of the viral integrase (IN) and interfere with the IN-viral RNA interaction during viral maturation. Here, we report a highly potent and safe pyrrolopyridine-based ALLINI, STP0404, displaying picomolar IC50 in human PBMCs with a >24,000 therapeutic index against HIV-1. X-ray structural and biochemical analyses revealed that STP0404 binds to the host LEDGF/p75 protein binding pocket of the IN dimer, which induces aberrant IN oligomerization and blocks the IN-RNA interaction. Consequently, STP0404 inhibits proper localization of HIV-1 RNA genomes in viral particles during viral maturation. Y99H and A128T mutations at the LEDGF/p75 binding pocket render resistance to STP0404. Extensive in vivo pharmacological and toxicity investigations demonstrate that STP0404 harbors outstanding therapeutic and safety properties. Overall, STP0404 is a potent and first-in-class ALLINI that targets LEDGF/p75 binding site and has advanced to a human trial.","journal":"PLoS Pathogens","year":2021,"id":159858,"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":39,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9531,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":671353,"name":"Seohyun Ahn","orcid":"0000-0003-4899-975X","position":1,"is_corresponding":false},{"id":671842,"name":"Uk-Il Kim","orcid":null,"position":2,"is_corresponding":false},{"id":422463,"name":"Jared Lindenberger","orcid":"0000-0003-2044-6715","position":3,"is_corresponding":false},{"id":314482,"name":"Adrian Oo","orcid":"0000-0002-2469-5391","position":4,"is_corresponding":false},{"id":324218,"name":"Pratibha C. Koneru","orcid":"0000-0003-3955-4548","position":5,"is_corresponding":false},{"id":451400,"name":"Bijan Mahboubi","orcid":"0000-0001-6480-7581","position":6,"is_corresponding":false},{"id":228712,"name":"Alan Engelman","orcid":"0000-0002-9709-2591","position":7,"is_corresponding":false},{"id":324221,"name":"Mamuka Kvaratskhelia","orcid":"0000-0003-3800-0033","position":8,"is_corresponding":false},{"id":671354,"name":"Kyungjin Kim","orcid":"0000-0002-8271-7640","position":9,"is_corresponding":false},{"id":252056,"name":"Baek Kim","orcid":"0000-0001-7986-4335","position":10,"is_corresponding":false},{"id":459764,"name":"Tatsuya Maehigashi","orcid":"0000-0002-9639-2250","position":0,"is_corresponding":true}],"reference_count":43,"raw_metadata":null,"created_at":"2026-07-18T23:44:39.550981Z","pmid":"34293041","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":[]}