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Cell Chem Biol. 2017 Aug 17;24(8):969-980.e4. doi: 10.1016/j.chembiol.2017.07.010. Epub 2017 Aug 10.

Aggregation and Its Influence on the Immunomodulatory Activity of Synthetic Innate Defense Regulator Peptides.

Author information

1
Center for Microbial Diseases and Immunity Research, Department of Microbiology and Immunology, University of British Columbia, #232, 2259 Lower Mall Research Station, Vancouver, BC V6T 1Z4, Canada.
2
Center for Microbial Diseases and Immunity Research, Department of Microbiology and Immunology, University of British Columbia, #232, 2259 Lower Mall Research Station, Vancouver, BC V6T 1Z4, Canada. Electronic address: bob@hancocklab.com.

Abstract

There is increasing interest in developing cationic host defense peptides (HDPs) and their synthetic derivatives as antimicrobial, immunomodulatory, and anti-biofilm agents. These activities are often evaluated without considering biologically relevant concentrations of salts or serum; furthermore certain HDPs have been shown to aggregate in vitro. Here we examined the effect of aggregation on the immunomodulatory activity of a synthetic innate defense regulator peptide, 1018 (VRLIVAVRIWRR-NH2). A variety of salts and solutes were screened to determine their influence on 1018 aggregation, revealing that this peptide "salts out" of solution in an anion-specific and concentration-dependent manner. Furthermore, the immunomodulatory activity of 1018 was found to be inhibited under aggregation-promoting conditions. A series of 1018 derivatives were synthesized with the goal of disrupting this self-assembly process. Indeed, some derivatives exhibited reduced aggregation while maintaining certain immunomodulatory functions, demonstrating that it is possible to engineer optimized synthetic HDPs to avoid unwanted peptide aggregation.

KEYWORDS:

aggregation; antimicrobial peptide; host defense peptide; immune modulator; peptide design; synthetic peptides

PMID:
28807783
DOI:
10.1016/j.chembiol.2017.07.010
[Indexed for MEDLINE]
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