{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T11:19:07Z","timestamp":1788434347068,"version":"build-2803163510"},"reference-count":47,"publisher":"American Chemical Society (ACS)","issue":"34","license":[{"start":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T00:00:00Z","timestamp":1787270400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T00:00:00Z","timestamp":1787270400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T00:00:00Z","timestamp":1787270400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["22276077"],"award-info":[{"award-number":["22276077"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["22476068"],"award-info":[{"award-number":["22476068"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,9,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Peptides are attractive molecular recognition elements because of their compact size, ease of modification, and structural tunability. The design of high-affinity peptides for small molecules lags far behind that of antibodies and aptamers due to the lack of general and effective discovery and optimization strategies. Computational design offers a promising avenue to overcome this bottleneck. Herein, we report a computational design pipeline, termed resampling\u2013iteration\u2013evolution (RIE), for the rapid discovery of high-affinity molecular recognition peptides (MRPs) from large structural and sequence databases. RIE mimics a top-down evolutionary pocket-narrowing process by resampling native three-dimensional binding architectures, preserving pocket cooperativity, and introducing rational mutations to generate affinity-enhanced variants. Using this strategy, we designed MRPs for folic acid (FA), triiodothyronine (T3), and cholic acid (CHD), highlighting its applicability to structurally diverse and clinically important small molecules. Despite being derived from 130\u2013270-residue protein receptors, the resulting 18-mer MRPs exhibited micromolar-level apparent Kd values of 8.0\u201312.7 \u03bcM in DMSO-based systems. By exploiting the small size and facile functionalization of MRPs, highly sensitive sensors for the rapid detection of small molecules were developed through flexible fluorophore modification. These results establish RIE as a rapid and effective in silico platform for the development of peptide binders for small-molecule targets.<\/jats:p>","DOI":"10.1021\/acs.analchem.6c02273","type":"journal-article","created":{"date-parts":[[2026,8,22]],"date-time":"2026-08-22T03:53:48Z","timestamp":1787370828000},"page":"24950-24963","source":"Crossref","is-referenced-by-count":0,"title":["Resampling\u2013Iteration\u2013Evolution (RIE):\nA Rational Design System for Engineering High-Affinity Peptides against\nSmall Molecules"],"prefix":"10.1021","volume":"98","author":[{"given":"Li-Hong","family":"Yu","sequence":"first","affiliation":[{"name":"Jiangnan University , , ,","place":["Wuxi, People\u2019s Republic of China, 214122"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun","family":"Ma","sequence":"additional","affiliation":[{"name":"Jiangnan University , , ,","place":["Wuxi, People\u2019s Republic of China, 214122"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue-Hong","family":"Pang","sequence":"additional","affiliation":[{"name":"Jiangnan University , , ,","place":["Wuxi, People\u2019s Republic of China, 214122"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3929-9228","authenticated-orcid":true,"given":"Xiao-Fang","family":"Shen","sequence":"additional","affiliation":[{"name":"Jiangnan University , , ,","place":["Wuxi, People\u2019s Republic of China, 214122"]},{"name":"Food Safety Detection Key Laboratory of Sichuan Province , ,","place":["Chengdu, People\u2019s Republic of China, 610041"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,21]]},"reference":[{"key":"2026090306475636900_cit1","doi-asserted-by":"publisher","first-page":"597","DOI":"10.1038\/s41586-021-03536-w","article-title":"Small-molecule inhibition of METTL3 as a strategy against myeloid\nleukaemia","volume":"593","author":"Yankova","year":"2021","journal-title":"Nature"},{"key":"2026090306475636900_cit2","doi-asserted-by":"publisher","first-page":"1338","DOI":"10.1126\/science.adm8684","article-title":"Targeting cancer with\nsmall-molecule pan-KRAS degraders","volume":"385","author":"Popow","year":"2024","journal-title":"Science"},{"key":"2026090306475636900_cit3","doi-asserted-by":"publisher","first-page":"3047","DOI":"10.1038\/s41467-025-58264-w","article-title":"Structural\nvisualization of small molecule recognition\nby CXCR3 uncovers dual-agonism in the CXCR3-CXCR7 system","volume":"16","author":"Saha","year":"2025","journal-title":"Nat. Commun."},{"key":"2026090306475636900_cit4","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1038\/s41392-022-01249-8","article-title":"Small molecules\nin the treatment of COVID-19","volume":"7","author":"Lei","year":"2022","journal-title":"Signal Transduction\nTargeted Ther."},{"key":"2026090306475636900_cit5","doi-asserted-by":"publisher","first-page":"10714","DOI":"10.1038\/s41467-024-55381-w","article-title":"Structural and functional determination of\npeptide versus small molecule ligand binding at the apelin receptor","volume":"15","author":"Williams","year":"2024","journal-title":"Nat. Commun."},{"key":"2026090306475636900_cit6","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1038\/s41392-023-01399-3","article-title":"Small molecule metabolites:\ndiscovery of biomarkers and therapeutic\ntargets","volume":"8","author":"Qiu","year":"2023","journal-title":"Signal Transduction Targeted Ther."},{"key":"2026090306475636900_cit7","doi-asserted-by":"publisher","first-page":"2392","DOI":"10.1039\/D2CS00070A","article-title":"Small molecule modulation of protein\npolymerization","volume":"51","author":"Fischer","year":"2022","journal-title":"Chem. Soc. Rev."},{"key":"2026090306475636900_cit8","doi-asserted-by":"publisher","first-page":"118137","DOI":"10.1016\/j.trac.2025.118137","article-title":"Peptide-based\nspecific biosensors for bioanalysis of\nhuman health","volume":"184","author":"Qin","year":"2025","journal-title":"Trends Anal. Chem."},{"issue":"11","key":"2026090306475636900_cit9","doi-asserted-by":"publisher","first-page":"2111","DOI":"10.1021\/acscentsci.4c01385","article-title":"High-affinity peptides for target\nprotein screened in ultralarge virtual libraries","volume":"10","author":"Xue","year":"2024","journal-title":"ACS Cent. 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Soc."},{"key":"2026090306475636900_cit32","doi-asserted-by":"publisher","first-page":"107895","DOI":"10.1016\/j.foodhyd.2022.107895","article-title":"Deciphering\nthe non-covalent binding patterns of three whey proteins with rosmarinic\nacid by multi-spectroscopic, molecular docking and molecular dynamics\nsimulation approaches","volume":"132","author":"Lu","year":"2022","journal-title":"Food Hydrocolloids"},{"key":"2026090306475636900_cit33","doi-asserted-by":"publisher","first-page":"741","DOI":"10.1016\/j.kint.2019.10.024","article-title":"The nucleic acid binding\nprotein YB-1-controlled expression of CXCL-1\nmodulates kidney damage in liver fibrosis","volume":"97","author":"Hermert","year":"2020","journal-title":"Kidney\nInt."},{"key":"2026090306475636900_cit34","doi-asserted-by":"publisher","first-page":"4087","DOI":"10.1021\/acs.biomac.0c00885","article-title":"Characterization of octreotide-PLGA\nbinding by isothermal titration calorimetry","volume":"21","author":"Hong","year":"2020","journal-title":"Biomacromolecules"},{"key":"2026090306475636900_cit35","doi-asserted-by":"publisher","first-page":"1918","DOI":"10.1261\/rna.057737.116","article-title":"A human microRNA\nprecursor\nbinding to folic acid discovered by small RNA transcriptomic SELEX","volume":"22","author":"Terasaka","year":"2016","journal-title":"RNA"},{"issue":"13","key":"2026090306475636900_cit36","doi-asserted-by":"publisher","first-page":"7150","DOI":"10.3390\/ijms23137150","article-title":"Triiodothyronine\nActs as a Smart Influencer on Hsp90 via a Triiodothyronine Binding\nSite","volume":"23","author":"Fan","year":"2022","journal-title":"Int. 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