Computer-Aided Design of Mastoparan-like Peptides Enables the Generation of Nontoxic Variants with Extended Antibacterial Properties

Autor(es):Mostrar menos -

Oshiro, Karen G. N. ^{[1, 2]} ; Candido, Elizabete S. ^{[2, 3]} ; Chan, Lai Y. ^[4] ; Torres, Marcelo D. T. ^{[5, 6, 7, 8, 9, 10, 11]} ; Monges, Bruna E. D. ^[2] ; Rodrigues, Silvia G. ^[2] ; Porto, William F. ^{[12, 2]} ; Ribeiro, Suzana M. ^[13] ; Henriques, Sonia T. ^[14] ; Lu, Timothy K. ; de la Fuente-Nunez, Cesar ^{[6, 7, 8, 9, 10]} ; Craik, David J. ^[4] ; Franco, Octavio L. ^{[1, 2, 3]} ; Cardoso, Marlon H. ^{[4, 1, 2, 3]}

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^[1] Univ Brasilia, Fac Med, Programa Posgrad Patol Mol, BR-70910900 Brasilia, DF - Brazil

^[2] Univ Catolica Dom Bosco, Programa Posgrad Biotecnol, S Inova Biotech, BR-79117900 Campo Grande - Brazil

^[3] Univ Catolica Brasilia, Posgrad Ciencias Genom & Biotecnol, Ctr Anal Proteom & Bioquim, BR-70790160 Brasilia, DF - Brazil

^[4] Univ Queensland, Inst Mol Biosci, Brisbane, Qld 4072 - Australia

^[5] Univ Fed ABC, Ctr Ciencias Nat & Humanas, BR-09210170 Santo Andre, SP - Brazil

^[6] MIT, Dept Elect Engn & Comp Sci, Cambridge, MA 02139 - USA

^[7] Univ Penn, Perelman Sch Med, Dept Psychiat, Philadelphia, PA 19104 - USA

^[8] Univ Penn, Dept Bioengn, Philadelphia, PA 19104 - USA

^[9] Univ Penn, Perelman Sch Med, Dept Microbiol, Philadelphia, PA 19104 - USA

^[10] MIT, Synthet Biol Ctr, Synthet Biol Grp, Res Lab Elect, Dept Biol Engn, Ctr Microbiome Infor, 77 Massachusetts Ave, Cambridge, MA 02139 - USA

^[11] Broad Inst & MIT Harvard, Cambridge, MA 02139 - USA

^[12] Porto Reports, BR-70790160 Brasilia, DF - Brazil

^[13] Fundacao Univ Fed Grande Dourados, Programa Posgrad Ciencias Saude, Dourados, MS 79825070 - Brazil

^[14] Queensland Univ Technol, Translat Res Inst, Fac Hlth, Sch Biomed Sci, Inst Hlth & Biomed Innovat, Brisbane, Qld 4102 - Australia

• Tipo de documento: Artigo Científico
• Fonte: Journal of Medicinal Chemistry; v. 62, n. 17, p. 8140-8151, SEP 12 2019.
• Citações Web of Science: 1

Resumo

Diverse peptides have been evaluated for their activity against pathogenic microorganisms. Here, five mastoparan variants were designed based on mastoparan-L, among which two (R1 and R4) were selected for in-depth analysis. Mastoparan-L (parent/control), R1, and R4 inhibited susceptible/resistant bacteria at concentrations ranging from 2 to 32 mu M, whereas only R1 and R4 eradicated Pseudomonas aeruginosa biofilms at 16 mu M. Moreover, the toxic effects of mastoparan-L toward mammalian cells were drastically reduced in both variants. In skin infections, R1 at 64 mu M was the most effective variant, reducing P. aeruginosa bacterial counts 1000 times on day 4 post-infection. Structurally, all of the peptides showed varying levels of helicity and structural stability in aqueous and membrane-like conditions, which may affect the different bioactivities observed here. By computationally modifying the physicochemical properties of R1 and R4, we reduced the cytotoxicity and optimized the therapeutic potential of these mastoparan-like peptides both in vitro and in vivo. (AU)

• Processo FAPESP: 14/04507-5 - Aplicações biológicas de novos peptídeos antimicrobianos
• Beneficiário: Marcelo Der Torossian Torres
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 16/24413-0 - Peptídeos anfipáticos catiônicos antimicrobianos e antibiofilmes
• Beneficiário: Marcelo Der Torossian Torres
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Doutorado