{"doi":"10.1016/j.chembiol.2024.01.010","title":"Allosteric inhibition of tRNA synthetase Gln4 by N-pyrimidinyl-β-thiophenylacrylamides exerts highly selective antifungal activity","abstract":"Candida species are among the most prevalent causes of systemic fungal infections, which account for ∼1.5 million annual fatalities. Here, we build on a compound screen that identified the molecule N-pyrimidinyl-β-thiophenylacrylamide (NP-BTA), which strongly inhibits Candida albicans growth. NP-BTA was hypothesized to target C. albicans glutaminyl-tRNA synthetase, Gln4. Here, we confirmed through in vitro amino-acylation assays NP-BTA is a potent inhibitor of Gln4, and we defined how NP-BTA arrests Gln4's transferase activity using co-crystallography. This analysis also uncovered Met496 as a critical residue for the compound's species-selective target engagement and potency. Structure-activity relationship (SAR) studies demonstrated the NP-BTA scaffold is subject to oxidative and non-oxidative metabolism, making it unsuitable for systemic administration. In a mouse dermatomycosis model, however, topical application of the compound provided significant therapeutic benefit. This work expands the repertoire of antifungal protein synthesis target mechanisms and provides a path to develop Gln4 inhibitors.","journal":"Cell chemical biology","year":2024,"id":463676,"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":5,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.956,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1241565,"name":"David Sychantha","orcid":"0000-0002-3497-1599","position":1,"is_corresponding":false},{"id":1294418,"name":"Elizabeth Lach","orcid":null,"position":2,"is_corresponding":false},{"id":1294041,"name":"Shawn Reeves","orcid":"0009-0004-8560-5021","position":3,"is_corresponding":false},{"id":747352,"name":"Sunna Nabeela","orcid":"0000-0002-8066-2199","position":4,"is_corresponding":false},{"id":866134,"name":"Meea Fogal","orcid":"0000-0002-0483-9626","position":5,"is_corresponding":false},{"id":841540,"name":"AkshatKumar Nigam","orcid":"0000-0002-5152-2082","position":6,"is_corresponding":false},{"id":1294042,"name":"Jarrod W. Johnson","orcid":"0000-0002-1214-6862","position":7,"is_corresponding":false},{"id":108074,"name":"Alán Aspuru‐Guzik","orcid":"0000-0002-8277-4434","position":8,"is_corresponding":false},{"id":841695,"name":"Rebecca S. Shapiro","orcid":"0000-0002-7119-8865","position":9,"is_corresponding":false},{"id":361370,"name":"Priya Uppuluri","orcid":"0000-0002-5889-054X","position":10,"is_corresponding":false},{"id":84363,"name":"Subha Kalyaanamoorthy","orcid":"0000-0003-0854-6449","position":11,"is_corresponding":false},{"id":510002,"name":"Jakob Magolan","orcid":"0000-0002-2947-8580","position":12,"is_corresponding":false},{"id":308242,"name":"Luke Whitesell","orcid":"0000-0001-6445-5766","position":13,"is_corresponding":false},{"id":308243,"name":"Nicole Robbins","orcid":"0000-0003-2821-9269","position":14,"is_corresponding":false},{"id":692339,"name":"Gerard D. Wright","orcid":"0000-0002-9129-7131","position":15,"is_corresponding":false},{"id":308244,"name":"Leah E. Cowen","orcid":"0000-0001-5797-0110","position":16,"is_corresponding":false},{"id":344686,"name":"Emily Puumala","orcid":"0009-0008-3371-5877","position":0,"is_corresponding":true}],"reference_count":107,"raw_metadata":null,"created_at":"2026-07-19T02:04:33.257852Z","pmid":"38402621","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":[]}