{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T01:17:47Z","timestamp":1772068667600,"version":"3.50.1"},"reference-count":66,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2023,4,27]],"date-time":"2023-04-27T00:00:00Z","timestamp":1682553600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"NIH-NHLBI","doi-asserted-by":"publisher","award":["K99 HL161423"],"award-info":[{"award-number":["K99 HL161423"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH-NHLBI","doi-asserted-by":"publisher","award":["P01 HL151333"],"award-info":[{"award-number":["P01 HL151333"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH-NHLBI","doi-asserted-by":"publisher","award":["R61 HL161813"],"award-info":[{"award-number":["R61 HL161813"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["K99 HL161423"],"award-info":[{"award-number":["K99 HL161423"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["P01 HL151333"],"award-info":[{"award-number":["P01 HL151333"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["R61 HL161813"],"award-info":[{"award-number":["R61 HL161813"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Cathepsin G (CatG) is a pro-inflammatory neutrophil serine protease that is important for host defense, and has been implicated in several inflammatory disorders. Hence, inhibition of CatG holds much therapeutic potential; however, only a few inhibitors have been identified to date, and none have reached clinical trials. Of these, heparin is a well-known inhibitor of CatG, but its heterogeneity and bleeding risk reduce its clinical potential. We reasoned that synthetic small mimetics of heparin, labeled as non-saccharide glycosaminoglycan mimetics (NSGMs), would exhibit potent CatG inhibition while being devoid of bleeding risks associated with heparin. Hence, we screened a focused library of 30 NSGMs for CatG inhibition using a chromogenic substrate hydrolysis assay and identified nano- to micro-molar inhibitors with varying levels of efficacy. Of these, a structurally-defined, octasulfated di-quercetin NSGM 25 inhibited CatG with a potency of ~50 nM. NSGM 25 binds to CatG in an allosteric site through an approximately equal contribution of ionic and nonionic forces. Octasulfated 25 exhibits no impact on human plasma clotting, suggesting minimal bleeding risk. Considering that octasulfated 25 also potently inhibits two other pro-inflammatory proteases, human neutrophil elastase and human plasmin, the current results imply the possibility of a multi-pronged anti-inflammatory approach in which these proteases are likely to simultaneously likely combat important conditions, e.g., rheumatoid arthritis, emphysema, or cystic fibrosis, with minimal bleeding risk.<\/jats:p>","DOI":"10.3390\/biom13050760","type":"journal-article","created":{"date-parts":[[2023,4,28]],"date-time":"2023-04-28T02:27:56Z","timestamp":1682648876000},"page":"760","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Homogeneous, Synthetic, Non-Saccharide Glycosaminoglycan Mimetics as Potent Inhibitors of Human Cathepsin G"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5675-1127","authenticated-orcid":false,"given":"Daniel K.","family":"Afosah","sequence":"first","affiliation":[{"name":"Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USA"},{"name":"Institute for Structural Biology, Drug Discovery and Development, Virginia Commonwealth University, Richmond, VA 23219, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rawan M.","family":"Fayyad","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USA"},{"name":"Institute for Structural Biology, Drug Discovery and Development, Virginia Commonwealth University, Richmond, VA 23219, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Valerie R.","family":"Puliafico","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, Washington and Lee University, Lexington, VA 24450, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Spencer","family":"Merrell","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, Washington and Lee University, Lexington, VA 24450, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eltice K.","family":"Langmia","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, Washington and Lee University, Lexington, VA 24450, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sophie R.","family":"Diagne","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Virginia Commonwealth University, Richmond, VA 23298, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9146-2662","authenticated-orcid":false,"given":"Rami A.","family":"Al-Horani","sequence":"additional","affiliation":[{"name":"Division of Basic Pharmaceutical Sciences, College of Pharmacy, Xavier University of Louisiana, New Orleans, LA 70125, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1976-6597","authenticated-orcid":false,"given":"Umesh R.","family":"Desai","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USA"},{"name":"Institute for Structural Biology, Drug Discovery and Development, Virginia Commonwealth University, Richmond, VA 23219, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.mib.2014.11.002","article-title":"Neutrophil Serine Proteases in Antibacterial Defense","volume":"23","author":"Stapels","year":"2015","journal-title":"Curr. 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