RESUMO
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.
Assuntos
Antimaláricos/farmacologia , Carbamatos/farmacologia , Cisteína Endopeptidases/metabolismo , Inibidores de Cisteína Proteinase/farmacologia , Dipeptídeos/farmacologia , Fenilalanina/análogos & derivados , Tripanossomicidas/farmacologia , Antimaláricos/síntese química , Antimaláricos/toxicidade , Carbamatos/síntese química , Carbamatos/toxicidade , Catepsina L/metabolismo , Inibidores de Cisteína Proteinase/síntese química , Inibidores de Cisteína Proteinase/toxicidade , Dipeptídeos/síntese química , Dipeptídeos/toxicidade , Células HeLa , Humanos , Ligação de Hidrogênio , Malária/tratamento farmacológico , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Doenças Negligenciadas/tratamento farmacológico , Fenilalanina/síntese química , Fenilalanina/farmacologia , Fenilalanina/toxicidade , Plasmodium falciparum/efeitos dos fármacos , Estereoisomerismo , Relação Estrutura-Atividade , Tripanossomicidas/síntese química , Tripanossomicidas/toxicidade , Trypanosoma brucei brucei/efeitos dos fármacos , Tripanossomíase Africana/tratamento farmacológicoRESUMO
A full polysaccharide amphiphilic block copolymer was prepared from end group-functionalized dextrans using copper-mediated azide-alkyne click chemistry. Sufficient modification of the reducing end in both blocks was achieved by microwave-enhanced reductive amination in a borate-buffer/methanol solvent system. The combination of a hydrophilic dextran block with a hydrophobic acetalated dextran block results in an amphiphilic structure that turns water-soluble upon acid treatment. The material has a low critical micelle concentration and self-assembles in water to spherical micellar nanoparticles. The formed nanoparticles have a narrow size distribution below 70 nm in diameter and disassemble in slightly acidic conditions. The amphiphilic polysaccharide system shows low toxicity and can stabilize the hydrophobic model drug curcumin in aqueous solutions over extended time periods.
