Abstract
This paper describes the development of a class of peptide-based inhibitors as novel antitrypanosomal and antimalarial agents. The inhibitors are based on a characteristic peptide sequence for the inhibition of the cysteine proteases rhodesain of Trypanosoma brucei rhodesiense and falcipain-2 of Plasmodium falciparum. We exploited the reactivity of novel unsaturated electrophilic functions such as vinyl-sulfones, -ketones, -esters, and -nitriles. The Michael acceptors inhibited both rhodesain and falcipain-2, at nanomolar and micromolar levels, respectively. In particular, the vinyl ketone 3b has emerged as a potent rhodesain inhibitor (k2nd = 67 × 106 M-1 min-1), endowed with a picomolar binding affinity (Ki = 38 pM), coupled with a single-digit micromolar activity against Trypanosoma brucei brucei (EC50 = 2.97 μM), thus being considered as a novel lead compound for the discovery of novel effective antitrypanosomal agents.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antimalarials / chemical synthesis
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Antimalarials / pharmacology*
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Antimalarials / toxicity
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Carbamates / chemical synthesis
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Carbamates / pharmacology*
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Carbamates / toxicity
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Cathepsin L / metabolism
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Cysteine Endopeptidases / metabolism*
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Cysteine Proteinase Inhibitors / chemical synthesis
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Cysteine Proteinase Inhibitors / pharmacology*
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Cysteine Proteinase Inhibitors / toxicity
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Dipeptides / chemical synthesis
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Dipeptides / pharmacology*
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Dipeptides / toxicity
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HeLa Cells
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Humans
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Hydrogen Bonding
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Malaria / drug therapy
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Molecular Docking Simulation
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Molecular Dynamics Simulation
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Neglected Diseases / drug therapy
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Phenylalanine / analogs & derivatives*
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Phenylalanine / chemical synthesis
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Phenylalanine / pharmacology
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Phenylalanine / toxicity
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Plasmodium falciparum / drug effects
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Stereoisomerism
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Structure-Activity Relationship
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Trypanocidal Agents / chemical synthesis
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Trypanocidal Agents / pharmacology*
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Trypanocidal Agents / toxicity
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Trypanosoma brucei brucei / drug effects
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Trypanosomiasis, African / drug therapy
Substances
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Antimalarials
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Carbamates
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Cysteine Proteinase Inhibitors
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Dipeptides
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Trypanocidal Agents
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benzyl (1-oxo-1-((6-oxo-1-phenylhept-4-en-3-yl)amino)-3-phenylpropan-2-yl)carbamate
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Phenylalanine
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Cysteine Endopeptidases
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falcipain 2
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rhodesain
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Cathepsin L