Immunomodulatory and antimicrobial properties of modified cationic peptides: IDR-1018 and IDR-1002

• Grant number: 15/15427-5
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• Effective date (Start): October 15, 2015
• Effective date (End): October 14, 2016
• Field of knowledge: Biological Sciences - Biochemistry - Chemistry of Macromolecules
• Principal Investigator: Osvaldo Novais de Oliveira Junior
• Grantee: Simone Cristina Barbosa
• Supervisor: Robert Ernest William Hancock
• Host Institution: Instituto de Física de São Carlos (IFSC). Universidade de São Paulo (USP). São Carlos , SP, Brazil
• Research place: University of British Columbia, Vancouver (UBC), Canada
• Associated to the scholarship: 14/03748-9 - ANTIMICROBIAL CYCLIC PEPTIDES: THE IMPORTANCE OF CYCLIC STRUCTURE OF THE MECHANISM OF ACTION OF TWO DIFFERENT STRUCTURES., BP.PD

Abstract

The increasing number of antibiotic-resistant bacteria calls for the development of new drugs. Antimicrobial peptides (AMPs) have a fast and lethal mechanism of action against microorganisms. AMPs' toxicity to human cells is small because they are attracted to the bacterial surface due to electrostatic interactions. A class of cationic peptides known as "innate defence regulator (IDR)" shows antimicrobial and immunomodulatory activities. The peptides IDR-1018 (VRLIVAVRIWRR-NH2) and IDR-1002 (VQRWLIVWRIRK-NH2) directly target biofilm cells while favorably modulate the immune response. Biofilms are able to cause infections and increase the host's adaptive resistance to conventional antibiotics. Currently, there are no approved drugs that target specifically bacterial biofilms. The potent anti-biofilm peptides 1018 and 1002 work by blocking ppGpp (Guanosine-tetraphosphate), an important signal in biofilm development. In this project, we propose to build analogue peptides with Arg and Lys substitution incorporating unnatural amino acids (Ornithine, homoarginine, 2-amino benzoate). The modified peptides will be studied for their immunomodulatory and anti-biofilm activities, and then compared to those of the unmodified IDR-1018 and 1002. Conformational changes, protease susceptibility, membrane interaction dynamics, and ability to aggregate will be compared and analyzed. The peptides developed are expected to be particularly advantageous for treating serious skin infections. (AU)