8CD9

Cathepsin B1 from Schistosoma mansoni in complex with gallinamide analog 6

This is a non-PDB format compatible entry.

Summary for 8CD9

• Entry DOI: 10.2210/pdb8cd9/pdb
• Related: 8CC2 8CCU
• Descriptor: Cathepsin B-like peptidase (C01 family), [(2~{S})-1-[[(2~{S})-1-[[(2~{S})-5-[(2~{S})-3-methoxy-5-oxidanylidene-2-(phenylmethyl)-2~{H}-pyrrol-1-yl]-5-oxidanylidene-pentan-2-yl]amino]-4-methyl-1-oxidanylidene-pentan-2-yl]amino]-4-methyl-1-oxidanylidene-pentan-2-yl] (2~{S})-2-(dimethylamino)-3-phenyl-propanoate, 1,2-ETHANEDIOL, ... (5 entities in total)
• Functional Keywords: cysteine protease, cathepsin b, smcb1, schistosoma mansoni, protease inhibitor peptidomimetic, gallinamide a, hydrolase
• Biological source: Schistosoma mansoni
• Total number of polymer chains: 1
• Total formula weight: 29297.21

Authors

Rubesova, P.,Brynda, J.,Fanfrlik, J.,Gerwick, W.H.,Mares, M. (deposition date: 2023-01-30, release date: 2024-02-21, Last modification date: 2024-10-09)

Primary citation

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, E.J.E.,Almaliti, J.,El-Sakkary, N.,Gerwick, W.H.,Caffrey, C.R.,Mares, M.
Nature-Inspired Gallinamides Are Potent Antischistosomal Agents: Inhibition of the Cathepsin B1 Protease Target and Binding Mode Analysis.
Acs Infect Dis., 10:1935-1948, 2024

PubMed Abstract: Schistosomiasis, caused by a parasitic blood fluke of the genus 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 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.

PubMed: 38757505
DOI: 10.1021/acsinfecdis.3c00589

Experimental method

X-RAY DIFFRACTION (1.55 Å)