7fbp
From Proteopedia
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Cyclotides are plant-derived peptides with complex structures shaped by their head-to-tail cyclic backbone and cystine knot core. These structural features underpin the native bioactivities of cyclotides, as well as their beneficial properties as pharmaceutical leads, including high proteolytic stability and cell permeability. However, their inherent structural complexity presents a challenge for cyclotide engineering, particularly for accessing libraries of sufficient chemical diversity to design potent and selective cyclotide variants. Here, we report a strategy using mRNA display enabling us to select potent cyclotide-based FXIIa inhibitors from a library comprising more than 10(12) members based on the cyclotide scaffold of Momordica cochinchinensis trypsin inhibitor-II (MCoTI-II). The most potent and selective inhibitor, cMCoFx1, has a pM inhibitory constant toward FXIIa with greater than three orders of magnitude selectivity over related serine proteases, realizing specific inhibition of the intrinsic coagulation pathway. The cocrystal structure of cMCoFx1 and FXIIa revealed interactions at several positions across the contact interface that conveyed high affinity binding, highlighting that such cyclotides are attractive cystine knot scaffolds for therapeutic development. | Cyclotides are plant-derived peptides with complex structures shaped by their head-to-tail cyclic backbone and cystine knot core. These structural features underpin the native bioactivities of cyclotides, as well as their beneficial properties as pharmaceutical leads, including high proteolytic stability and cell permeability. However, their inherent structural complexity presents a challenge for cyclotide engineering, particularly for accessing libraries of sufficient chemical diversity to design potent and selective cyclotide variants. Here, we report a strategy using mRNA display enabling us to select potent cyclotide-based FXIIa inhibitors from a library comprising more than 10(12) members based on the cyclotide scaffold of Momordica cochinchinensis trypsin inhibitor-II (MCoTI-II). The most potent and selective inhibitor, cMCoFx1, has a pM inhibitory constant toward FXIIa with greater than three orders of magnitude selectivity over related serine proteases, realizing specific inhibition of the intrinsic coagulation pathway. The cocrystal structure of cMCoFx1 and FXIIa revealed interactions at several positions across the contact interface that conveyed high affinity binding, highlighting that such cyclotides are attractive cystine knot scaffolds for therapeutic development. | ||
| - | An Ultrapotent and Selective Cyclic Peptide Inhibitor of Human beta-Factor XIIa in a Cyclotide Scaffold.,Liu W, de Veer SJ, Huang YH, Sengoku T, Okada C, Ogata K, Zdenek CN, Fry BG, Swedberg JE, Passioura T, Craik DJ, Suga H J Am Chem Soc. 2021 Nov 10;143(44):18481-18489. doi: 10.1021/jacs.1c07574. Epub, 2021 Nov 1. PMID:34723512<ref>PMID:34723512</ref> | + | An Ultrapotent and Selective Cyclic Peptide Inhibitor of Human beta-Factor XIIa in a Cyclotide Scaffold.,Liu W, de Veer SJ, Huang YH, Sengoku T, Okada C, Ogata K, Zdenek CN, Fry BG, Swedberg JE, Passioura T, Craik DJ, Suga H J Am Chem Soc. 2021 Nov 10;143(44):18481-18489. doi: 10.1021/jacs.1c07574. Epub , 2021 Nov 1. PMID:34723512<ref>PMID:34723512</ref> |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
Current revision
FXIIa-cMCoFx1 complex
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Categories: Homo sapiens | Large Structures | Synthetic construct | Craik DJ | Fry BG | Huang YH | Liu W | Ogata K | Okada C | Passioura T | Sengoku T | Suga H | Swedberg JE | Zdenek CN | De Veer SJ
