BACKGROUND:  Defensins are cysteine-rich, cationic antimicrobial peptides expressed by leukocytes and epithelial cells of mammals and birds. These peptides, which can be considered endogenous antibiotics, play an important role in innate host defense against pathogens due to their antibacterial, antifungal and antiviral activities. Three defensin subfamilies exist in vertebrates: alpha-defensins, beta-defensins, and theta (circular) minidefensins. All of these have largely beta-sheet structures that are stabilized by three intramolecular cystine disulfide bonds, and derive from a common ancestral gene. Theta defensins are much smaller (18 amino acid residues) than alpha or beta defensins (29-45 residues), and their antiviral properties are considerably more robust than their antibacterial and antifungal effects.

INNOVATION: Retrocyclins 1 and 2 (also called RC-100 and RC100b) are novel circular peptides discovered by UCLA Researchers. Although they are produced synthetically, their structures are based on nucleotide sequences found in the human genome and/or in mRNA expressed by human bone marrow. Since human theta-defensin genes and retrocyclin bone marrow mRNA contain a premature stop codon in their signal sequence, retrocyclin peptides are probably not produced in humans. However, these peptides are found in certain Old World monkeys, and intact theta defensin genes are also present in lesser apes and orangutans (unpublished). Although the ability of theta defensins to kill bacteria is relatively modest, retrocyclin 1 and especially retrocyclin-2 show impressive activity against three different viral pathogens: human immunodeficiency virus (HIV-1), herpes simplex virus-1 and herpes simplex virus-2 (HSV-2). Although such broad specificity is somewhat reminiscent of interferons, retrocyclins operate as entry inhibitors. Retrocyclin-2 showed activity against a wide library of primary HIV-1 isolates of diverse subtypes, including subtypes A, B, C, CRF01, D, G, and recombinant subtypes. Its effectiveness was not dependent on or restricted by co-receptor (R5, X4 or R5X4) usage. The UCLA researchers are using retrocyclins-1 and 2 as platforms to develop analogs with improved pharmacotherapeutic properties.

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