Intramolecular interactions enhance the potency of gallinamide A analogs against Trypanosoma cruzi
Intramolecular interactions enhance the potency of gallinamide A analogs against Trypanosoma cruzi
ABSTRACT Gallinamide A, a metabolite of the marine cyanobacterium Schizothrix sp., selectively inhibits cathepsin L-like cysteine proteases. We evaluated potency of gallinamide A and 23 synthetic analogs against intracellular Trypanosoma cruzi amastigotes and the cysteine protease, cruzain. We determined the co-crystal structures of cruzain with gallinamide A and two synthetic analogs at ～2?. SAR data revealed that the N-terminal end of gallinamide A is loosely bound and weakly contributes in drug-target interactions. At the C-terminus, the intramolecular π?π stacking interactions between the aromatic substituents at P1’ and P1 restrict the bioactive conformation of the inhibitors, thus minimizing the entropic loss associated with target binding. Molecular dynamics simulations showed that in the absence of an aromatic group at P1, the substituent at P1’ interacts with tryptophan-184. The P1-P1’ interactions had no effect on anti-cruzain activity whereas anti-T. cruzi potency increased by ～5-fold, likely due to an increase in solubility/permeability of the analogs.
Da Silva Elany Barbosa、Sharma Vandna、Stoye Alexander、O?ˉDonoghue Anthony J.、Payne Richard J.、Podust Larissa M.、McKerrow James H.、Hernandez-Alvarez Lilian、Tang Arthur H.、Gerwick William H.
Skaggs School of Pharmacy and Pharmaceutical Sciences, Center for Discovery and Innovation in Parasitic Diseases, University of California San DiegoSkaggs School of Pharmacy and Pharmaceutical Sciences, Center for Discovery and Innovation in Parasitic Diseases, University of California San DiegoSchool of Chemistry, The University of Sydney||Australian Research Council Centre of Excellence for Innovations in Peptide and Protein ScienceSkaggs School of Pharmacy and Pharmaceutical Sciences, Center for Discovery and Innovation in Parasitic Diseases, University of California San DiegoSchool of Chemistry, The University of Sydney||Australian Research Council Centre of Excellence for Innovations in Peptide and Protein ScienceSkaggs School of Pharmacy and Pharmaceutical Sciences, Center for Discovery and Innovation in Parasitic Diseases, University of California San DiegoSkaggs School of Pharmacy and Pharmaceutical Sciences, Center for Discovery and Innovation in Parasitic Diseases, University of California San DiegoSkaggs School of Pharmacy and Pharmaceutical Sciences, Center for Discovery and Innovation in Parasitic Diseases, University of California San Diego||Departamento de F¨asica, Instituto de Bioci¨oncias, Letras e Ci¨oncias Exatas, Universidade Estadual Paulista Julio de Mesquita FilhoSchool of Chemistry, The University of Sydney||Australian Research Council Centre of Excellence for Innovations in Peptide and Protein ScienceSkaggs School of Pharmacy and Pharmaceutical Sciences, Center for Discovery and Innovation in Parasitic Diseases, University of California San Diego||Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography. University of California San Diego
医药卫生理论药学分子生物学
Da Silva Elany Barbosa,Sharma Vandna,Stoye Alexander,O?ˉDonoghue Anthony J.,Payne Richard J.,Podust Larissa M.,McKerrow James H.,Hernandez-Alvarez Lilian,Tang Arthur H.,Gerwick William H..Intramolecular interactions enhance the potency of gallinamide A analogs against Trypanosoma cruzi[EB/OL].(2025-03-28)[2025-05-31].https://www.biorxiv.org/content/10.1101/2021.12.22.473926.点此复制
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