Peptide-Based Drug Design

128 Hilpert et al.
Key Words: Screening; high-throughput; SPOT synthesis; cellulose; luminescence;
Pseudomonas aeruginosa; QSAR; antimicrobial; antibacterial; peptide; machine learning;
artificial neural networks.
1. Cationic Antimicrobial Peptides
Cationic antimicrobial peptides, also called cationic host defense peptides, are
present in virtually every form of life, from bacteria and fungi to plants, invertebrates,
and vertebrates (1). They support bacteria and fungi in the defense of their
ecological niche. In addition to ribosomally produced peptides, many microbes
are able to synthesize powerful antimicrobial peptides by using multienzyme
complexes (2). These complexes are able to build peptides with nonproteogenic
amino acids or catalyze unusual modifications. Antimicrobial peptides like
polymyxin B and gramicidin S are examples of such modified peptides. Antimicrobial
peptides have been found in plants that were active against bacteria
and fungi. Until now only peptides with a �-sheet globular structure have been
isolated from plants (3). More structurally diverse peptides have been found in
invertebrates. Invertebrates are reliant on the innate immunity, of which antimicrobial
peptides are a critical part. In invertebrates, antimicrobial peptides are
found in the hemolymph, in phagocytic cells, and in different epithelial cells
and show activities against bacteria, yeast, and viruses (4). Intensive studies
have been conducted on antimicrobial peptides and their role in innate immune
system on the invertebrates: fruit fly, as well as horseshoe crabs (5–7). Ithas
only recently become apparent that the adaptive immune system arose in jawed
vertebrates, but little is known about the deeper origins of this system or the
relationship with the innate immune system in invertebrates (8,9). Invertebrates,
antimicrobial peptides are found mainly at the skin and mucosal surfaces
and within granules of immune cells (10,11). For example, amphibian skin is
a rich source of antimicrobial peptides, e.g., the skin of the frog Odorrana
grahami contains 107 different antimicrobial peptides (12). Studies on antimicrobial
peptides of mammals, including human, have revealed that besides the
direct antimicrobial activity, some peptides also influence the immune system.
These particular peptides are able to counter sepsis/entotoxemia, enhance phagocytosis,
recruit various immune cells, and increase or decrease the production of
cytokines and chemokines in different cell types (13).
Despite the variety of different sources, sequences and structures, all cationic
antimicrobial peptides share some common features: small size (12–50 amino
acids), positive net charge (+2 to +9), amphiphilic (≥30% hydrophobic
amino acids) and antimicrobial and/or immunomodulatory activity. Some
cationic antimicrobial peptides also show antiviral (14) and/or anticancer
activity (15) as well as wound healing properties (16). More than 1000