Host Defense Peptides Research Laboratory

Prof. Amram Mor

two types of lipopeptides (SMALLs and ROAKs) destined to generate novel alternatives to antibiotics and bacteria capturing filters, respectively

Introduction:

The fundamental interest of the lab members is in designing new peptide-based therapeutic strategies towards treating bacterial infections, in the light of globally increasing antibiotic resistance. Our research program focuses on developing multidisciplinary tactics for studying the multiform peptide function in biological systems. Typically, we perform structure-activity relationships (SAR) studies, using rational design approaches for biological or chemical synthesis of structural analogs; we characterize the interactions with target sites (membranes, proteins and nucleic acids of pro- and eu-karyotes); we assess effect(s) and delivery mechanisms in culture and in animal models of disease.

Main Contributions to Science:

By isolating and characterizing the first members of one of the largest families of host defense peptides (i.e., the dermaseptins), we contributed to establish the ubiquitous role of host defense peptides (HDPs) as a component of the innate immune system of practically all living organisms. Our subsequent structure-activity relationships studies of the dermaseptins have contributed to shed light into the peptides biological roles and have established peptide-based antimicrobials as a powerful investigative tool that portrays a highly manageable synthetic system for targeting a wide spectrum of pathogens and likely to significantly escape the known drug resistance mechanisms.

Implementation of our findings in de-novo design of HDP chemical mimics resulted in a novel family of synthetic peptidomimetics: Oligomers of Acylated Cations (OACs) presenting various advantages. SAR studies of the original OACs contributed to establish quantitative relationships between the most critical chemo-physical attributes for HDP and OAC properties, i.e., charge (Q) and hydrophobicity (H) (aka, QH window) defining minimum requirements for selective antibacterial activity. In addition to their potential usefulness in fighting bacterial infections, OACs have shown anticancer and antimalarial efficacies in cultures and in mouse models for the respective induced diseases.

Recent studies were focused on exploiting OACs lipophilic properties for developing new tactics susceptible to overcome antibiotic-resistance mechanisms, thereby restoring sensitivity phenotypes and widening the activity spectrum of classical antibiotics to include Gram-negative species endowed with efflux-based drug resistance. Namely, these studies led to the design of short, membrane-active, lipopeptide-like (SMALL) sequences with improved PK/PD properties and enhanced potential applications in systemic treatment of infectious diseases, by directly targeting Gram-positive and/or Gram-negative bacteria.

Our most recent efforts focus on developing the ability of new non-antibiotic SMALL versions to sensitize pathogenic bacteria to conventional antibiotics as well as the host innate immune system and to their combination.