Simplified θ-Defensins: Search for New Antivirals

The Chemistry and Biology of Theta Defensins

“…Examples include pseudogene products, Lys mutants to enable labeling with chromophores, Tyr mutants, and retro‐ and enantioanalogues for anti‐HIV and carbohydrate‐binding studies 86. 87 Chemical synthesis has also been used to produce simplified retrocyclin analogues,88 disulfide‐bond analogues, and θ‐defensin analogues containing non‐native bioactive epitopes 76. 77 Oxidation of unprotected cysteine residues appears to give the native I–VI, II–V, III–IV (laddered) disulfide connectivity 76.…”

“…Cells and chicken embryos transfected with retrocyclin‐2 showed reduced infection with H5N1 avian influenza virus, but it was not clear whether the cells expressed cyclic retrocyclin 109. Chemically synthesized truncated θ‐defensin analogues have also shown anti‐influenza A activity 88. 110 Furthermore, a series of θ‐defensins and analogues inhibited the entry of herpes simplex virus into cells by binding surface glycoproteins111 and retrocyclin‐2 was effective as a prophylaxis against herpes simplex virus type 1 in a keratitis mouse model 112…”

Chemie und Biologie von Theta‐Defensinen

“…Beispiele hierfür sind Pseudogenprodukte, Lys‐Mutanten für Markierungen mit Chromophoren, Tyr‐Mutanten und Retro‐ sowie Enantioanaloga zur Untersuchung ihrer Anti‐HIV‐Aktivität und der Bindung von Kohlenhydraten 86. 87 Chemische Synthesen wurden außerdem zur Erzeugung vereinfachter Retrocyclinanaloga88 sowie von Disulfidbindungs‐ und θ‐Defensinanaloga mit nichtnatürlichen bioaktiven Epitopen verwendet 76. 77 Die Oxidation ungeschützter Cysteinreste scheint die natürliche I‐VI‐, II‐V‐und III‐IV‐Disulfidverknüpfung (in Form einer Leiter) zu ergeben 76.…”

“…Mit Retrocyclin‐2 transfizierte Zellen und Hühnerembryos zeigten eine verminderte Infektion mit dem Vogelgrippevirus H5N1, es war aber unklar, ob die Zellen cyclisches Retrocyclion exprimierten 109. Chemisch synthetisierte, verkürzte θ‐Defensinanaloga waren ebenfalls wirksam gegen Influenza A 88. 110 Außerdem inhibierte eine Serie von θ‐Defensinen und Analoga den Zelleintritt des Herpes‐simplex‐Virus durch Binden von Oberflächenglycoproteinen,111 und Retrocyclin‐2 war ein effektives Mittel zur Prophylaxe gegen das Herpes‐simplex‐Virus des Typs 1 in einem Mausmodell für Keratitis 112…”

Antimicrobial Peptides: Their History, Evolution, and Functional Promiscuity

“…Moreover, based on the evolutionary divergence of Hominoidea from Cercopithecoidea, this would suggest that θ-defensins are at least 30 million years old [202,203]. Interestingly, the pseudogenes of human θ-defensins, or retrocyclins, have been successfully expressed in human cells by using aminoglycosides to bypass the premature stop codon of their mRNA [201,204] and have been shown to have potent antiviral activity [205], particular against HIV [204,206,207]. Given that viruses have evolved in the absence of selective pressures from retrocyclins, it has been proposed that restoration of the endogenous production of these peptides in human cervicovaginal tissues by the application of aminoglycoside-based topical microbicides may help prevent the sexual transmission of HIV [201,204].…”