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

Author(s):Show less -

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]}

Affiliation

^[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

• Document type: Journal article
• Source: COMMUNICATIONS BIOLOGY; v. 1, 2018.
• Web of Science Citations: 16

Abstract

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)

• FAPESP's process: 14/04507-5 - Biological applications of new antimicrobial peptides
• Grantee: Marcelo Der Torossian Torres
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 16/24413-0 - Antimicrobial and antibiofilm cationic amphipathic peptides
• Grantee: Marcelo Der Torossian Torres
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• FAPESP's process: 14/12938-6 - Biologically active peptides against pathogenic micro-organisms
• Grantee: Vani Xavier de Oliveira Junior
• Support Opportunities: Regular Research Grants