Structure-function-guided exploration of the antimicrobial peptide polybia-CP identifies activity determinants and generates synthetic therapeutic candidates

Autor(es):Mostrar menos -

Torres, Marcelo D. T. ^{[1, 2, 3, 4, 5, 6]} ; Pedron, Cibele N. ^[1] ; Higashikuni, Yasutomi ^{[2, 3, 4, 5, 6]} ; Kramer, Robin M. ^[7] ; Cardoso, Marlon H. ^{[8, 9, 10]} ; Oshiro, Karen G. N. ^[10] ; Franco, Octavio L. ^{[8, 9, 10]} ; Silva Junior, I, Pedro ; Silva, Fernanda D. ^[1] ; Oliveira Junior, Vani X. ^[1] ; Lu, Timothy K. ^{[2, 3, 4, 5, 6]} ; de la Fuente-Nunez, Cesar ^{[2, 3, 4, 5, 6]}

Afiliação do(s) autor(es)

^[1] Univ Fed ABC, Ctr Ciencias Nat & Humanas, BR-09210580 Santo Andre, SP - Brazil

^[2] MIT, Dept Elect Engn & Comp Sci, Cambridge, MA 02139 - USA

^[3] MIT, Ctr Microbiome Informat & Therapeut, 77 Massachusetts Ave, Cambridge, MA 02139 - USA

^[4] MIT, Synthet Biol Grp, MIT Synthet Biol Ctr, 77 Massachusetts Ave, Cambridge, MA 02139 - USA

^[5] MIT, Res Lab Elect, Dept Biol Engn, 77 Massachusetts Ave, Cambridge, MA 02139 - USA

^[6] Brd Inst MIT & Harvard, Cambridge, MA 02142 - USA

^[7] MIT, Div Comparat Med, Cambridge, MA 02139 - USA

^[8] Univ Brasilia, Fac Med, Programa Posgrad Patol Mol, BR-70297400 Brasilia, DF - Brazil

^[9] Univ Catolica Brasilia, Ctr Anal Prote & Bioquim, BR-71966700 Brasilia, DF - Brazil

^[10] Univ Catolica Dom Bosco, S Inova Biotech, Programa Posgrad Biotecnol, BR-79117010 Campo Grande, MS - Brazil

• Tipo de documento: Artigo Científico
• Fonte: COMMUNICATIONS BIOLOGY; v. 1, 2018.
• Citações Web of Science: 16

Resumo

Antimicrobial peptides (AMPs) constitute promising alternatives to classical antibiotics for the treatment of drug-resistant infections, which are a rapidly emerging global health challenge. However, our understanding of the structure-function relationships of AMPs is limited, and we are just beginning to rationally engineer peptides in order to develop them as therapeutics. Here, we leverage a physicochemical-guided peptide design strategy to identify specific functional hotspots in the wasp-derived AMP polybia-CP and turn this toxic peptide into a viable antimicrobial. Helical fraction, hydrophobicity, and hydrophobic moment are identified as key structural and physicochemical determinants of antimicrobial activity, utilized in combination with rational engineering to generate synthetic AMPs with therapeutic activity in a mouse model. We demonstrate that, by tuning these physicochemical parameters, it is possible to design nontoxic synthetic peptides with enhanced sub-micromolar antimicrobial potency in vitro and anti-infective activity in vivo. We present a physicochemical-guided rational design strategy to generate peptide antibiotics. (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
• Processo FAPESP: 14/12938-6 - Peptídeos biologicamente ativos em micro-organismos patogênicos
• Beneficiário: Vani Xavier de Oliveira Junior
• Modalidade de apoio: Auxílio à Pesquisa - Regular