{"doi":"10.1021/acs.biochem.4c00854","title":"Inhibitors of SAMHD1 Obtained from Chemical Tethering to the Guanine Antiviral Acyclovir","abstract":"Sterile alpha motif histidine-aspartate domain protein 1 (SAMHD1) is an enzyme with diverse activities. Its dNTPase activity degrades all canonical dNTPs and many anticancer nucleoside drugs, while its single-stranded nucleic acid binding activity promotes DNA repair and RNA homeostasis in cells. These functions require guanine nucleotide binding to a specific allosteric site (A1) on the enzyme. We previously described how the activities of SAMHD1 could be inhibited in vitro with fragment-based inhibitor design, using dGMP as a targeting fragment for the A1 site. However, these dGMP-tethered inhibitors had poor cell permeability due to the charged guanine monophosphate group. Here, we describe a new approach where the amino form of the guanine acyclic nucleoside acyclovir (NH 2 -ACV) is used as the targeting fragment, allowing facile coupling to activated carboxylic acids (R–COOH), either directly or using linkers. This approach generates a neutral amide instead of charged monophosphate attachment points. High-throughput screening of a ∼375 compound carboxylic acid library identified two compounds ( 8, 11 ) with similar micromolar affinities for SAMHD1. Compound 11 was obtained by direct coupling to NH 2 -ACV, while compound 8 used a five-carbon linker. Both inhibitors had the same dibromonaphthol component from the carboxylic acid library screen. A crystal structure of a complex between SAMHD1 and 8, combined with computational models of bound 11, suggest how the dibromonaphthol promotes binding. The findings establish that guanine-based inhibitors targeting the A1 site do not require nucleotide or cyclic nucleoside structural elements. This guanine site targeting strategy is highly amenable to further chemical optimization.","journal":"Biochemistry","year":2025,"id":531998,"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":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9588,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":140568,"name":"Shridhar Bhat","orcid":null,"position":1,"is_corresponding":false},{"id":770358,"name":"A. Hasan Howlader","orcid":"0000-0001-7864-2722","position":2,"is_corresponding":false},{"id":337482,"name":"Mario A. Bianchet","orcid":"0000-0001-9032-7549","position":3,"is_corresponding":false},{"id":1412790,"name":"Yi Liu","orcid":"0000-0002-3710-2073","position":4,"is_corresponding":false},{"id":1413255,"name":"Laura Rovira","orcid":null,"position":5,"is_corresponding":false},{"id":1044073,"name":"Brandon Smith","orcid":"0009-0008-1714-5990","position":6,"is_corresponding":false},{"id":387543,"name":"Marc M. Greenberg","orcid":"0000-0002-5786-6118","position":7,"is_corresponding":false},{"id":454788,"name":"James T. Stivers","orcid":"0000-0003-2572-7807","position":8,"is_corresponding":false},{"id":733621,"name":"Matthew Egleston","orcid":"0000-0002-6601-7425","position":0,"is_corresponding":true}],"reference_count":34,"raw_metadata":null,"created_at":"2026-07-19T02:51:18.928280Z","pmid":"39989431","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":[]}