Cathelicidin antimicrobial peptide

The term was coined in 1995 from cathelin, due to the characteristic cathelin-like domain present in cathelicidins. The name cathelin itself is coined from cathepsin L inhibitor in 1989. ==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. 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. == Other activities ==

LL-37 plays a role in the activation of cell proliferation and migration, contributing to the wound closure process. All these mechanisms together play an essential role in tissue homeostasis and regenerative processes. Moreover, it has an agonistic effect on various pleiotropic receptors, for example, formyl peptide receptor like-1 (FPRL-1), purinergic receptor P2X7, epidermal growth factor receptor (EGFR). Furthermore, it induces angiogenesis and regulates apoptosis. ==Characteristics==

Cathelicidins range in size from 12 to 80 amino acid residues and have a wide range of structures. Most cathelicidins are linear peptides with 23-37 amino acid residues, and fold into amphipathic α-helices. Additionally cathelicidins may also be small-sized molecules (12-18 residues) with beta-hairpin structures, stabilized by one or two disulphide bonds. Even larger cathelicidin peptides (39-80 amino acid residues) are also present. These larger cathelicidins display repetitive proline motifs forming extended polyproline-type structures. The cathelicidin family shares primary sequence homology with the cystatin family of cysteine proteinase inhibitors, although amino acid residues thought to be important in such protease inhibition are usually lacking. Cleavage products LL-37 is cleaved into a number of smaller fragments which retain anti-microbial and anti-cancer effects but generally have a lower toxicity to human cells. RK-31, KS-30 and KR-20 are naturally occurring fragments, while other related peptides have been made synthetically based on natural fragments of LL-37 during research into cathelicidins, and in some cases have amino acid substitutions. 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. Antibodies to the human LL-37/hCAP-18 have been used to find cathelicidin-like compounds in a marsupial. About 30 cathelicidin family members have been described in mammals, with only one (LL-37) found in humans. • Rats: • Rabbits: CAP-18 • Guinea pig: CAP-11 • Pigs: PR-39, Prophenin, PMAP-23,36,37 • Cattle: BMAP-27,28,34 (Bovine Myeloid Antimicrobial Peptides); Bac5, Bac7 • Frogs: cathelicidin-AL (found in Amolops loloensis) • Chickens: Four cathelicidins, fowlicidins 1,2,3 and cathelicidin Beta-1 • Tasmanian Devil: Saha-CATH5 • Salmonids: CATH1 and CATH2 == Clinical significance ==

Patients with rosacea have elevated levels of cathelicidin and elevated levels of stratum corneum tryptic enzymes (SCTEs). Cathelicidin is cleaved into the antimicrobial peptide LL-37 by both kallikrein 5 and kallikrein 7 serine proteases. Excessive production of LL-37 is suspected to be a contributing cause in all subtypes of Rosacea. Antibiotics have been used in the past to treat rosacea, but antibiotics may only work because they inhibit some SCTEs. Lower plasma levels of human cathelicidin antimicrobial protein (hCAP18) appear to significantly increase the risk of death from infection in dialysis patients. The production of cathelicidin is up-regulated by vitamin D. 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. In addition, SAAP-148 synergises with the repurposed antibiotic halicin against antibiotic-resistant bacteria and biofilms. LL-37 is thought to play a role in psoriasis pathogenesis (along with other anti-microbial peptides). In psoriasis, damaged keratinocytes release LL-37 which forms complexes with self-genetic material (DNA or RNA) from other cells. These complexes stimulate dendritic cells (a type of antigen presenting cell) which then release interferon α and β which contributes to differentiation of T-cells and continued inflammation. LL-37 has also been found to be a common auto-antigen in psoriasis; T-cells specific to LL-37 were found in the blood and skin in two thirds of patients with moderate to severe psoriasis. == 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. 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. Research into new and improved variations derived from cathelicidin continues. == See also ==