{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Kadivella M"],"funding":["Department of Biotechnology, Ministry of Science and Technology (DBT)"],"pagination":["1382"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC12480558"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["8(1)"],"pubmed_abstract":["Monophosphoryl lipid A (MPLA), a TLR4 agonist, is a clinically approved vaccine adjuvant, but its complex structure and occasional toxicity limit broader use. Synthetic small-molecule TLR4 agonists offer advantages such as ease of synthesis, lower cost, and reduced toxicity. In this study, we conducted structure-based virtual screening of the ZINC database to identify novel TLR4-targeting small molecules across human, murine, and bovine species. Three lead compounds-NSF-418, NSF-501, and NSF-951-were selected based on favorable binding interactions and subjected to in vitro and in vivo evaluation. NSF-951 emerged as a potent TLR4 agonist, inducing strong proinflammatory cytokine responses (IL-6, TNF-α), upregulating CD80 and CD86 expression, and promoting macrophage maturation. Conversely, NSF-418 and NSF-501 acted as antagonists by suppressing MPLA-induced responses. In murine immunization studies, NSF-951, alone or with Alum (AF007), significantly enhanced OVA-specific antibody and T-cell responses without observable toxicity. These findings suggest that NSF-951 is a promising, cost-effective TLR4 agonist with strong immunostimulatory and adjuvant potential. Further studies are warranted to assess its performance with other antigens and adjuvant combinations, supporting its development as a next-generation adjuvant for veterinary and human vaccines."],"journal":["Communications biology"],"pubmed_title":["Adjuvant activity of a small molecule TLR4 agonist discovered via structure-based virtual screening."],"pmcid":["PMC12480558"],"funding_grant_id":["BT/PR34488/MED/15/221/2022(SP094)"],"pubmed_authors":["Faisal SM","Cp J","Azam S","Varma VP","Kadivella M","Kavela S"],"additional_accession":[]},"is_claimable":false,"name":"Adjuvant activity of a small molecule TLR4 agonist discovered via structure-based virtual screening.","description":"Monophosphoryl lipid A (MPLA), a TLR4 agonist, is a clinically approved vaccine adjuvant, but its complex structure and occasional toxicity limit broader use. Synthetic small-molecule TLR4 agonists offer advantages such as ease of synthesis, lower cost, and reduced toxicity. In this study, we conducted structure-based virtual screening of the ZINC database to identify novel TLR4-targeting small molecules across human, murine, and bovine species. Three lead compounds-NSF-418, NSF-501, and NSF-951-were selected based on favorable binding interactions and subjected to in vitro and in vivo evaluation. NSF-951 emerged as a potent TLR4 agonist, inducing strong proinflammatory cytokine responses (IL-6, TNF-α), upregulating CD80 and CD86 expression, and promoting macrophage maturation. Conversely, NSF-418 and NSF-501 acted as antagonists by suppressing MPLA-induced responses. In murine immunization studies, NSF-951, alone or with Alum (AF007), significantly enhanced OVA-specific antibody and T-cell responses without observable toxicity. These findings suggest that NSF-951 is a promising, cost-effective TLR4 agonist with strong immunostimulatory and adjuvant potential. Further studies are warranted to assess its performance with other antigens and adjuvant combinations, supporting its development as a next-generation adjuvant for veterinary and human vaccines.","dates":{"release":"2025-01-01T00:00:00Z","publication":"2025 Sep","modification":"2026-06-04T01:46:38.68Z","creation":"2026-05-04T03:13:46.618Z"},"accession":"S-EPMC12480558","cross_references":{"pubmed":["41023411"],"doi":["10.1038/s42003-025-08582-y"]}}