Cathelicidin antimicrobial peptide

Cathelicidin antimicrobial peptide (CAMP) is an

The cathelicidin family includes 30 types of which LL-37 is the only cathelicidin in the human.[3] Cathelicidins are stored in the secretory granules of neutrophils and macrophages and can be released following activation by leukocytes.^[4] Cathelicidin peptides are dual-natured molecules called amphiphiles: one end of the molecule is attracted to water and repelled by fats and proteins, and the other end is attracted to fat and proteins and repelled by water. Members of this family react to pathogens by disintegrating, damaging, or puncturing cell membranes.

Cathelicidins thus serve a critical role in mammalian innate immune defense against invasive bacterial infection.^[5] The cathelicidin family of peptides are classified as antimicrobial peptides (AMPs). The AMP family also includes the defensins. Whilst the defensins share common structural features, cathelicidin-related peptides are highly heterogeneous.^[5] Members of the cathelicidin family of antimicrobial polypeptides are characterized by a highly conserved region (cathelin domain) and a highly variable cathelicidin peptide domain.^[5]

Cathelicidin peptides have been isolated from many different species of

The term was coined in 1995 from cathelin, due to the characteristic cathelin-like domain present in cathelicidins.[10] The name cathelin itself is coined from cathepsin L inhibitor in 1989.^[11]

Mechanism of antimicrobial activity

The general rule of the mechanism triggering cathelicidin action, like that of other antimicrobial peptides, involves the disintegration (damaging and puncturing) of cell membranes of organisms toward which the peptide is active.^[4] Antimicrobial effects have been observed against fungal, bacterial, and viral pathogens.^{[citation needed]}

Cathelicidins rapidly destroy the lipoprotein membranes of microbes enveloped in phagosomes after fusion with lysosomes in macrophages. Therefore, LL-37 can inhibit the formation of bacterial biofilms.^[12]

Other activities

LL-37 plays a role in the activation of cell proliferation and migration, contributing to the wound closure process.

Furthermore, it induces angiogenesis^[17] and regulates apoptosis.^[18] These processes are dysregulated during tumor development, and thus LL-37 might be involved in pathogenesis of malignant tumors.^{[citation needed]}

Characteristics

Cathelicidins range in size from 12 to 80 amino acid residues and have a wide range of structures.

In 1995, Gudmundsson et al. assumed that the active antimicrobial peptide is formed of a 39-residue C-terminal domain (termed FALL-39). However, only a year later stated that the matured AMP, now called LL-37, is in reality two amino acids shorter than FALL-39.[20]^[21]

The cathelicidin family shares primary sequence homology with the cystatin^[22] family of cysteine proteinase inhibitors, although amino acid residues thought to be important in such protease inhibition are usually lacking.

Non-human orthologs

Cathelicidin peptides have been found in humans, monkeys, mice, rats, rabbits, guinea pigs, pandas, pigs, cattle, frogs, sheep, goats, chickens, horses and wallabies.^[23] Antibodies to the human LL-37/hCAP-18 have been used to find cathelicidin-like compounds in a marsupial.^[24] About 30 cathelicidin family members have been described in mammals, with only one (LL-37) found in humans.^[4] Currently identified cathelicidin peptides include the following:^[5]

Clinical significance

Patients with

SAAP-148 (a synthetic antimicrobial and antibiofilm peptide) is a modified version of LL-37 that has enhanced antimicrobial activities compared to LL-37. In particular, SAAP-148 was more efficient in killing bacteria under physiological conditions.[34] In addition, SAAP-148 synergises with the repurposed antibiotic halicin against antibiotic-resistant bacteria and biofilms.^[35]

LL-37 is thought to play a role in

LL-37 binds to the peptide Ab, which is associated with Alzheimer's disease. An imbalance between LL-37 and Ab may be a factor affecting AD-associated fibrils and plaques. Chronic, oral Porphyromonas gingivalis, and herpesvirus (HSV-1) infections may contribute to the progression of Alzheimer's dementia.^[37][38]

Applications

Research into the AMP family—particularly in regards to their mechanism of action—has been ongoing for nearly 20 years. Despite sustained interest, treatments derived or utilizing AMPs have not been widely adopted for clinical use for several reasons.^[39] One, drug candidates from AMPs have a narrow window of bioavailability, because peptides are quickly broken down by proteases. Two, peptide drugs are more expensive than small molecule drugs to produce, which is problematic since peptide drugs must be given in large doses to counter rapid enzymatic breakdown. These qualities also limit routes of administration, typically to injection, infusion, or slow release therapy.^[40]

See also

• Antimicrobial peptides
• Innate immune system
• Peptoid

References