Abstract
The increasing resistance of bacteria to conventional antibiotics has encouraged strong efforts to develop new antimicrobial agents. In addition, exposure to biological warfare agents may cause highly progressive, acute infections that may be lethal. Unfortunately, an attack by biological warfare agents may go unnoticed until large groups of people begin
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exhibiting symptoms and diagnosis is not always possible. Therefore, the early use of broad-spectrum antibiotics might be life saving. Host defense peptides (HDPs) are widely considered to be excellent lead structures for the development of novel broad-spectrum antibiotics because of their broad-spectrum of antimicrobial activity. In addition, they can modulate the innate immune response and boost infection-resolving immunity, while dampening potentially harmful pro-inflammatory (septic) responses. In order to develop artificial variants of HDPs with optimized activity for therapeutic application in depth understanding of the structure-activity relationship (SAR) is crucial. We identified the minimal LPS-neutralizing domain of the best studied HDP in man, LL-37, by using a library with overlapping sequences. Correlations between the capacity of LL-37 fragments to modulate TLR responses and their physico-chemical properties revealed that cationicity and hydrophobicity are essential for the modulation of LL-37 mediated TLR responses. A similar approach was used to evaluate the structure-activity relationship of the newly discovered HDP chicken cathelicidin-2 (CATH-2), revealing that core elements within mature CATH-2 can be identified that are linked to antibacterial and/or immunomodulatory activities. The antibacterial activity is located in a relatively short segment of the N-terminus of the peptide while the immunomodulatory activity is located in the central area of the peptide. In this respect, the N-terminal segment is of particular interest to use as a template for further development, because it combines high antibacterial activity with low cytotoxicity. The N-terminal part of CATH-2, C1-15, was used as a paradigm to develop very small, stable peptides with improved antibacterial and endotoxin-neutralizing activities. Point mutations which induced slight changes in hydrophobicity of the peptides increased antibacterial or immunomodulatory activity. We conclude that CATH-2 derived peptides are effective antibacterial and anti-inflammatory agents in vitro and can potentially be used as lead molecules for the development of novel drugs for the control of infectious diseases. D-isomers and head-to-tail cyclic variants of these peptides may potentially enhance their therapeutic efficacy.
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