Peptide-Based Drug Design

10 Bulet
Key Words: Invertebrate immunity; antimicrobial peptides; immune effectors; mass
spectrometry; drug discovery; Drosophila; arthropods; peptide purification; molecular mass
fingerprints; bioactive peptides.
1. Introduction
To date, three major classes of molecules have been developed for
the treatment of human diseases. These types of molecules are small
molecules, protein drugs, and peptides. Currently, most of the therapeutic
molecules developed and marketed are small molecules. However, with the
recent advancements in several technologies in the areas of (1) peptide
manufacturing (chemical synthesis, recombinant expression), (2) screening, (3)
stability, (4) modifications, and (5) improvements in peptide drug delivery
systems, peptides are now considered as lead molecules for therapeutics
(http://pubs.acs.org/cen/business/83/i11/8311bus1.html). Nature is an unlimited
pipeline of bioactive peptides that are active regulators, information/signaling
factors, and key components of the defense reactions, properties that make
them interesting for drug discovery and development. Among the peptides, the
bioactive peptides from the defense mechanisms of living organisms have such
a therapeutic potential (1–4). Host-defense peptides are widely distributed in
nature. Bacteria produce peptide antibiotics to mediate their microbial competitions
(5,6). In multicellular organisms from both the vegetal and animal
kingdoms, host-defense peptides such as antimicrobial peptides (AMPs) form a
first line of host defense against pathogens (7–11). AMPs are critical effectors of
the innate immunity of many species and are playing an essential role in terms
of resistance to infection and survival. In living organisms, AMPs were found
to be either constitutively stored or produced upon infection (natural or experimental).
In invertebrates, for example, AMPs were found to be stored in immune
competent blood cells (hemocytes) and in epithelial cells of a range of tissues.
Interestingly, the presence of AMPs and other immune defense molecules in
the hemolymph (the blood of invertebrates) or at the surface of the epithelia
is only present if an infection is detected (12–17). AMPs were also reported
to be constituents of the venom of arthropods (18). In addition to AMPs, a
variety of other immune-induced molecules are produced to clear microbial
infections; this was illustrated in the fruit fly model, Drosophila melanogaster
(19–21). Therefore, together with other effectors of invertebrate immunity, they
are considered potential candidates for their development as therapeutic drugs or
as markers for diagnosis with applications in disease control. Such a distribution
within body fluids (hemolymph but also venom) or immunocompetent cells,
which is dependant of an immune state, is particularly important to consider