8cd9

Cathepsin B1 from Schistosoma mansoni in complex with gallinamide analog 6

spinqualitylabelsall models 8cd9, resolution 1.55Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8cd9 is a 1 chain structure with sequence from Schistosoma mansoni. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.55Å Ligands: EDO, NA, UA9 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function Q8MNY2_SCHMA Publication Abstract from PubMed Schistosomiasis, caused by a parasitic blood fluke of the genus Schistosoma, is a global health problem for which new chemotherapeutic options are needed. We explored the scaffold of gallinamide A, a natural peptidic metabolite of marine cyanobacteria that has previously been shown to inhibit cathepsin L-type proteases. We screened a library of 19 synthetic gallinamide A analogs and identified nanomolar inhibitors of the cathepsin B-type protease SmCB1, which is a drug target for the treatment of schistosomiasis mansoni. Against cultured S. mansoni schistosomula and adult worms, many of the gallinamides generated a range of deleterious phenotypic responses. Imaging with a fluorescent-activity-based probe derived from gallinamide A demonstrated that SmCB1 is the primary target for gallinamides in the parasite. Furthermore, we solved the high-resolution crystal structures of SmCB1 in complex with gallinamide A and its two analogs and describe the acrylamide covalent warhead and binding mode in the active site. Quantum chemical calculations evaluated the contribution of individual positions in the peptidomimetic scaffold to the inhibition of the target and demonstrated the importance of the P1' and P2 positions. Our study introduces gallinamides as a powerful chemotype that can be exploited for the development of novel antischistosomal chemotherapeutics. Nature-Inspired Gallinamides Are Potent Antischistosomal Agents: Inhibition of the Cathepsin B1 Protease Target and Binding Mode Analysis.,Spiwokova P, Horn M, Fanfrlik J, Jilkova A, Fajtova P, Leontovyc A, Houstecka R, Bielikova L, Brynda J, Chanova M, Mertlikova-Kaiserova H, Caro-Diaz EJE, Almaliti J, El-Sakkary N, Gerwick WH, Caffrey CR, Mares M ACS Infect Dis. 2024 Jun 14;10(6):1935-1948. doi: 10.1021/acsinfecdis.3c00589. , Epub 2024 May 17. PMID:38757505 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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