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3. Druggable Hot Spots in the Schistosomiasis Cathepsin B1 Target Identified by Functional and Binding Mode Analysis of Potent Vinyl Sulfone Inhibitors

Author

Jílková, Adéla, primary, Rubešová, Petra, additional, Fanfrlík, Jindřich, additional, Fajtová, Pavla, additional, Řezáčová, Pavlína, additional, Brynda, Jiří, additional, Lepšík, Martin, additional, Mertlíková-Kaiserová, Helena, additional, Emal, Cory D., additional, Renslo, Adam R., additional, Roush, William R., additional, Horn, Martin, additional, Caffrey, Conor R., additional, and Mareš, Michael, additional

Published
2020
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12. Structure-Activity Relationships for Inhibition of Cysteine Protease Activity and Development of Plasmodium falciparumby Peptidyl Vinyl Sulfones

Author

Shenai, Bhaskar R., Lee, Belinda J., Alvarez-Hernandez, Alejandro, Chong, Pek Y., Emal, Cory D., Neitz, R. Jeffrey, Roush, William R., and Rosenthal, Philip J.

Abstract

ABSTRACTThe Plasmodium falciparumcysteine proteases falcipain-2 and falcipain-3 appear to be required for hemoglobin hydrolysis by intraerythrocytic malaria parasites. Previous studies showed that peptidyl vinyl sulfone inhibitors of falcipain-2 blocked the development of P. falciparumin culture and exerted antimalarial effects in vivo. We now report the structure-activity relationships for inhibition of falcipain-2, falcipain-3, and parasite development by 39 new vinyl sulfone, vinyl sulfonate ester, and vinyl sulfonamide cysteine protease inhibitors. Levels of inhibition of falcipain-2 and falcipain-3 were generally similar, and many potent compounds were identified. Optimal antimalarial compounds, which inhibited P. falciparumdevelopment at low nanomolar concentrations, were phenyl vinyl sulfones, vinyl sulfonate esters, and vinyl sulfonamides with P2leucine moieties. Our results identify independent structural correlates of falcipain inhibition and antiparasitic activity and suggest that peptidyl vinyl sulfones have promise as antimalarial agents.

Published
2003
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13. Druggable Hot Spots in the Schistosomiasis Cathepsin B1 Target Identified by Functional and Binding Mode Analysis of Potent Vinyl Sulfone Inhibitors.

Author

Jílková A, Rubešová P, Fanfrlík J, Fajtová P, Řezáčová P, Brynda J, Lepšík M, Mertlíková-Kaiserová H, Emal CD, Renslo AR, Roush WR, Horn M, Caffrey CR, and Mareš M

Subjects
Animals, Humans, Schistosoma mansoni, Sulfones pharmacology, Cathepsin B, Schistosomiasis drug therapy
Abstract

Schistosomiasis, a parasitic disease caused by blood flukes of the genus Schistosoma , is a global health problem with over 200 million people infected. Treatment relies on just one drug, and new chemotherapies are needed. Schistosoma mansoni cathepsin B1 (SmCB1) is a critical peptidase for the digestion of host blood proteins and a validated drug target. We screened a library of peptidomimetic vinyl sulfones against SmCB1 and identified the most potent SmCB1 inhibitors reported to date that are active in the subnanomolar range with second order rate constants ( k 2nd ) of ∼2 × 10 5 M -1 s -1 . High resolution crystal structures of the two best inhibitors in complex with SmCB1 were determined. Quantum chemical calculations of their respective binding modes identified critical hot spot interactions in the S1' and S2 subsites. The most potent inhibitor targets the S1' subsite with an N -hydroxysulfonic amide moiety and displays favorable functional properties, including bioactivity against the pathogen, selectivity for SmCB1 over human cathepsin B, and reasonable metabolic stability. Our results provide structural insights for the rational design of next-generation SmCB1 inhibitors as potential drugs to treat schistosomiasis.

Published
2021
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