In Vitro and In Vivo Anti-Candida Activity and Structural Analysis of Killer Peptide (KP)-Derivatives.

Tecla Ciociola,Tiziana D'Adda,Tiziano De Simone,Thelma A Pertinhez,Walter Magliani,Stefania Conti,Laura Giovati,Elena Ferrari,Silvana Belletti

doi:10.3390/jof7020129

Abstract

The previously described decapeptide AKVTMTCSAS (killer peptide, KP), derived from the variable region of a recombinant yeast killer toxin-like anti-idiotypic antibody, proved to exert a variety of antimicrobial, antiviral, and immunomodulatory activities. It also showed a peculiar self-assembly ability, likely responsible for the therapeutic effect in animal models of systemic and mucosal candidiasis. The present study analyzed the biological and structural properties of peptides derived from KP by substitution or deletion of the first residue, leaving unchanged the remaining amino acids. The investigated peptides proved to exert differential in vitro and/or in vivo anti-Candida activity without showing toxic effects on mammalian cells. The change of the first residue in KP amino acidic sequence affected the conformation of the resulting peptides in solution, as assessed by circular dichroism spectroscopy. KP-derivatives, except one, were able to induce apoptosis in yeast cells, like KP itself. ROS production and changes in mitochondrial transmembrane potential were also observed. Confocal and transmission electron microscopy studies allowed to establish that selected peptides could penetrate within C. albicans cells and cause gross morphological alterations. Overall, the physical and chemical properties of the first residue were found to be important for peptide conformation, candidacidal activity and possible mechanism of action. Small antimicrobial peptides could be exploited for the development of a new generation of antifungal drugs, given their relative low cost and ease of production as well as the possibility of devising novel delivery systems.

Highlights

In the last few decades, the attention of scientists, public health officials, governments, and general public has again focused on infectious diseases, due to emerging and re-emerging etiological agents, including multidrug-resistant pathogens [1,2,3,4]
The spread of resistant microorganisms has not seen a simultaneous increase in the availability of new antimicrobials [5]
The work started from the decapeptide AKVTMTCSAS (A10S, killer peptide KP)

Summary

Introduction

In the last few decades, the attention of scientists, public health officials, governments, and general public has again focused on infectious diseases, due to emerging and re-emerging etiological agents, including multidrug-resistant pathogens [1,2,3,4]. The spread of resistant microorganisms has not seen a simultaneous increase in the availability of new antimicrobials [5]. In this scenario, a number of alternative anti-infective strategies are being developed [6,7,8,9,10], including the exploitation of proteins and peptides as possible substitutes of conventional anti-infective drugs [11,12]. In particular, on the anti-infective properties of synthetic peptides whose sequence represents fragments of variable and constant regions of antibodies (Ab) [24]. A peculiar self-assembly ability was demonstrated for KP, likely responsible for its therapeutic activity in vivo, that characterizes this peptide as a prototype of auto-delivering drugs [27]

Objectives

Methods

Results

Conclusion