Highly Constrained Bicyclic Scaffolds for the Discovery of Protease-Stable Peptides via mRNA Display.
Highly constrained peptides such as the knotted peptide natural products are promising medicinal agents because of their impressive biostability and potent activity. Yet, libraries of highly constrained peptides are challenging to prepare. Here, we present a method which utilizes two robust, orthogonal chemical steps to create highly constrained bicyclic peptide libraries. This technology was optimized to be compatible with in vitro selections by mRNA display. We performed side-by-side monocyclic and bicyclic selections against a model protein (streptavidin). Both selections resulted in peptides with mid-nanomolar affinity, and the bicyclic selection yielded a peptide with remarkable protease resistance.
Virginia Commonwealth University , Department of Chemistry, 1001 West Main Street, Richmond, Virginia 23284-2006, United States.|National Center for Biotechnology Information , 8600 Rockville Pike, Bethesda, Maryland 20894, United States.
David E
DE
Hacker
Virginia Commonwealth University , Department of Chemistry, 1001 West Main Street, Richmond, Virginia 23284-2006, United States.|National Center for Biotechnology Information , 8600 Rockville Pike, Bethesda, Maryland 20894, United States.
Jan
J
Hoinka
Virginia Commonwealth University , Department of Chemistry, 1001 West Main Street, Richmond, Virginia 23284-2006, United States.|National Center for Biotechnology Information , 8600 Rockville Pike, Bethesda, Maryland 20894, United States.
Emil S
ES
Iqbal
Virginia Commonwealth University , Department of Chemistry, 1001 West Main Street, Richmond, Virginia 23284-2006, United States.|National Center for Biotechnology Information , 8600 Rockville Pike, Bethesda, Maryland 20894, United States.
Teresa M
TM
Przytycka
Virginia Commonwealth University , Department of Chemistry, 1001 West Main Street, Richmond, Virginia 23284-2006, United States.|National Center for Biotechnology Information , 8600 Rockville Pike, Bethesda, Maryland 20894, United States.
Matthew C T
0000-0003-0210-1422
MC
Hartman
D001643:Bridged Bicyclo Compounds / Q000737:chemistry*; D057930:Click Chemistry; D010447:Peptide Hydrolases / Q000737:chemistry*; D010455:Peptides / Q000737:chemistry*; D019809:Streptavidin / Q000737:chemistry
D001643:Bridged Bicyclo Compounds; D010455:Peptides; D019809:Streptavidin; D010447:Peptide Hydrolases