Chimerical peptides neutralizing the cytotoxicity caused by Stx2 toxin produced by Escherichia coli

• Grant number: 14/03529-5
• Support type: Scholarships in Brazil - Post-Doctorate
• Effective date (Start): October 01, 2014
• Effective date (End): July 07, 2018
• Field of knowledge: Biological Sciences - Microbiology - Applied Microbiology
• Cooperation agreement: Coordination of Improvement of Higher Education Personnel (CAPES)
• Principal researcher: Tomomasa Yano
• Grantee: Robert Alvin Bernedo Navarro
• Home Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated scholarship(s): 15/22937-0 - Identification of neutralizing Shiga toxin 2 nanobodies from immune phage display library, BE.EP.PD

Abstract

Shiga toxin-producing Escherichia coli (STEC) is a group of enteric pathogens causing diseases in humans such as diarrhea, hemorrhagic colitis and hemolytic uremic syndrome. The virulence factor that defines the STEC strains is the production of potent cytotoxins that inhibit the protein synthesis, called Shiga toxins (Stx). Recently, our research group described the development of peptides neutralizing the cytotoxicity caused by toxins Stx1 and Stx2. Our group also demonstrated that using the Gb3 receptor as a target for the screening of phage display libraries is a promissory alternative in searching of molecules neutralizing Stx -induced cytotoxicity. Three peptides have been described with potential for neutralizing Stx -induced cytotoxicity in vitro. In studies with mice the peptides inhibit the lethality caused by Stx1, however, none of the described peptides inhibited Stx2-induced lethality. The Stx2 toxin has been associated more often with the most severe clinical symptoms in humans. The Stx toxins are formed by one subunit (StxA) with enzymatic activity and five identical B subunits (StxB) involved in the binding of Stx to Gb3 receptor. In the absence of the subunit StxA, the STxB pentamer adopts a structure that is functionally equivalent to the complete toxin binding to Gb3 receptor. Due to these reasons, the aim of this project is to develop bivalent chimerical peptides with neutralizing potential for cytotoxicity caused by Stx2 toxin and bind both the Gb3 receptor subunit as will Stx2B. To identify the individual peptide phage display approach described by fellowship candidate will be used. (AU)