In Silico Identification and Biological Evaluation of Antimicrobial Peptides Based on Human Cathelicidin LL-37
2006 (English)In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 50, no 9, 2983-2989 p.Article in journal (Refereed) Published
Bacterial lipopolysaccharides (LPS) are important triggers of the widespread inflammatory response, which contributes to the development of multiple organ failure during sepsis. The helical 37-amino-acid-long human antimicrobial peptide LL-37 not only possesses a broad-spectrum antimicrobial activity but also binds and neutralizes LPS. However, the use of LL-37 in sepsis treatment is hampered by the fact that it is also cytotoxic. To find a less toxic analog of LL-37, we used in silico analysis to identify amphipathic helical regions of LL-37. A 21-amino-acid fragment (GKE) was synthesized, the biological actions of which were compared to those of two equally long peptides derived from the N and C termini of LL-37 as well as native LL-37. GKE displayed antimicrobial activity against Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Candida albicans, and Candida parapsilosis that was similar to or even stronger than LL-37. GKE, as well as the equally long control peptides, attracted granulocytes in a fashion similar to that of LL-37, while only GKE was as potent as LL-37 in inhibiting LPS-induced vascular nitric oxide production. GKE caused less hemolysis and apoptosis in human cultured smooth muscle cells than LL-37. In summary, we have identified an active domain of LL-37, GKE, which displays antimicrobial activity in vitro and LPS-binding activity similar to those of LL-37 but is less toxic. GKE therefore holds promise as a template for the development of peptide antibiotics for the treatment of sepsis.
Place, publisher, year, edition, pages
2006. Vol. 50, no 9, 2983-2989 p.
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:uu:diva-81955DOI: 10.1128/AAC.01583-05ISI: 000240297000013PubMedID: 16940092OAI: oai:DiVA.org:uu-81955DiVA: diva2:109870