RESUMO
Peptide modification with fatty acids is an effective method to improve peptide performance. We previously investigated the fatty acid modification of R-lycosin-I, a cytotoxic peptide derived from lycosin-I from the venom of the spider Lycosa singoriensis. In this study, we further investigated the position effects of fatty acid modification of lycosin-I. Dodecanoic acid was covalently coupled to the α/ε-amino group of one of the seven Lys residues of lycosin-I, generating eight different lipopeptides. Although all the lipopeptides had significantly improved cytotoxicity compared with lycosin-I, they displayed different cytotoxic potencies and profiles, which might be explained by multifactors including charge, size, helicity, hydrophobicity, and so forth. Of the eight lipopeptides, L-C12 demonstrated highest cytotoxicity and antimetastasis activity in two-dimensional cells, tumor spheroids, subcutaneous transplantation mouse models, and experimental melanoma metastasis mouse models. Collectively, our finding indicated that fatty acid modification position plays important roles in physiochemical parameters and biological activities of cytotoxic peptides.
Assuntos
Peptídeos Catiônicos Antimicrobianos/farmacologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Ácidos Graxos/química , Lipopeptídeos/farmacologia , Neoplasias Pulmonares/secundário , Melanoma Experimental/patologia , Venenos de Aranha/farmacologia , Animais , Peptídeos Catiônicos Antimicrobianos/química , Antineoplásicos/química , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Humanos , Interações Hidrofóbicas e Hidrofílicas , Lipopeptídeos/química , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Melanoma Experimental/tratamento farmacológico , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Venenos de Aranha/química , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Glycoconjugation is a promising modification strategy for the optimization of peptide drugs. In this study, five different monosaccharide derivatives (7a-e) were covalently linked to the N-terminal of R-lycosin-I, which yielded five glycopeptides (8a-e). They demonstrated increased or reduced cytotoxicity depending on monosaccharide types, which might be explained by the changes of physicochemical properties. Among all synthesized glycopeptides, only 8a exhibited increased cytotoxicity (IC50 = 9.6 ± 0.3 µM) and selectivity (IC50 = 37.4 ± 5.9 µM). The glucose transporter 1 (GLUT1) with high expression in cancer cells was approved to be involved in the cytotoxicity and selectivity enhancement of 8a. Furthermore, 8a but not R-lycosin-I inhibited tumor growth in the nude mice xenograft model without generating side effects intraperitoneally. Taken together, this study reveals the different monosaccharide roles in peptide modification and also provides an optimized anticancer peptide with high activity and selectivity, that is, 8a might be a promising lead for developing anticancer drugs.