Mechanistic and Structural Basis of Bioengineered Bovine Cathelicidin-5 with Optimized Therapeutic Activity

Overview

Journal Sci Rep

Specialty Science

Date 2017 Mar 22

PMID 28322271

Citations 7

Authors

Bikash R Sahoo

Kenta Maruyama

Jyotheeswara R Edula

Takahiro Tougan

Yuxi Lin

Young-Ho Lee

Toshihiro Horii

Toshimichi Fujiwara

Affiliations

Soon will be listed here.

Abstract

Peptide-drug discovery using host-defense peptides becomes promising against antibiotic-resistant pathogens and cancer cells. Here, we customized the therapeutic activity of bovine cathelicidin-5 targeting to bacteria, protozoa, and tumor cells. The membrane dependent conformational adaptability and plasticity of cathelicidin-5 is revealed by biophysical analysis and atomistic simulations over 200 μs in thymocytes, leukemia, and E. coli cell-membranes. Our understanding of energy-dependent cathelicidin-5 intrusion in heterogeneous membranes aided in designing novel loss/gain-of-function analogues. In vitro findings identified leucine-zipper to phenylalanine substitution in cathelicidin-5 (1-18) significantly enhance the antimicrobial and anticancer activity with trivial hemolytic activity. Targeted mutants of cathelicidin-5 at kink region and N-terminal truncation revealed loss-of-function. We ensured the existence of a bimodal mechanism of peptide action (membranolytic and non-membranolytic) in vitro. The melanoma mouse model in vivo study further supports the in vitro findings. This is the first structural report on cathelicidin-5 and our findings revealed potent therapeutic application of designed cathelicidin-5 analogues.

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