nNOS inhibition, antimicrobial and anticancer activity of the amphibian skin peptide, citropin 1.1 and synthetic modifications

Abstract

A large number of bioactive peptides have been isolated from amphibian skin secretions. These peptides have a variety of actions including antibiotic and anticancer activities and the inhibition of neuronal nitric oxide synthase. We have investigated the structure-activity relationship of citropin 1.1, a broad-spectrum antibiotic and anticancer agent that also causes inhibition of neuronal nitric oxide synthase, by making a number of synthetically modified analogues. Citropin 1.1 has been shown previously to form an amphipathic a-helix in aqueous trifluoroethanol. The results of the structure-activity studies indicate the terminal residues are important for bacterial activity and increasing the overall positive charge, while maintaining an amphipathic distribution of residues, increases activity against Gram-negative organisms. Anticancer activity generally mirrors antibiotic activity suggesting a common mechanism of action. The N-terminal residues are important for inhibition of neuronal nitric oxide synthase, as is an overall positive charge greater than three. The structure of one of the more active synthetic modifications (A4K14-citropin 1.1) was determined in aqueous trifluoroethanol, showing that this peptide also forms an amphipathic a-helix.

Anticancer activity of a synthetic peptide derived from harmoniasin, an antibacterial peptide from the ladybug Harmonia axyridis

“…In previous studies, α-helical peptides were shown to need more than 20 amino acid residues to span the entire thickness of the eukaryotic cell membranes for the barrel-stave mechanism (29,30). Thus, the relatively small size of HaA4 along with aurein 1.2 (31) and citropin 1.1 (32), isolated from frogs suggest that these AMPs mediate their membranolytic effect through the carpet mechanism (33). In addition, it has been reported that bovine lactoferricin binds to the cell membrane and causes cell membrane disruption followed by entry of the peptide to the cytoplasm of Jurkat T-leukemia cells and damage to mitochondrial membrane (34).…”

In Vitro Activity and Killing Effect of Uperin 3.6 against Gram-Positive Cocci Isolated from Immunocompromised Patients

“…The structural diversity of polypeptides secreted from amphibian dermal granular glands is probably reflective of a plethora of different biological functions, including the regulation of skin physiology, defense against predators, or prevention of skin colonization/infection by microorganisms (1). Of particular note has been the focused effort, during the last decade, of several studies which have reported the host defense peptides exuded in secretions from dorsal glands of some 20 species of Australian anurans, including species from the genera Litoria and Uperoleia (3,5,18). Uperin 3.6 is a wide-spectrum antibiotic peptide isolated from the Australian toadlet Uperoleia mjobergii.…”

“…Uperin 3.6 is one of the most potent membrane-active antimicrobial peptides isolated from amphibians. It adopts an amphipathic ␣-helical structure along its entire length with no central region of enhanced flexibility, a feature commonly found in cationic peptides (3,5,18).…”

Investigation of the cytocidal potential ofRhinella jimiskin methanol extracts

“…Natural products of other amphibian as Bombina variegate have demonstrated interesting results against several types of neoplastic cell lines (Doyle et al, 2003;Kamano et al, 2002). The extract of the skin and the secretions of other amphibian species Bufo bufo gargarizans Cantor (Bufonidae) are used in the preparation of the Chinese traditional remedy Chan Su, used against several illnesses and with an antineoplastic activity reported by several articles, mainly due the alkaloid bufagin, a natural product that can affect several mechanisms involved on the cell proliferation (Hashimoto et al, 1997;Akiyama et al, 1999;Yeh et al, 2003;Nasu et al, 2005).…”