Retrocyclins: Cyclic mini-defensins that inactivate anthrax toxins

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Broad, Long Term Obiectives: To discover new drugs ("minidefensins") for treating bacterial and viral infections, based on theta-defensins, unique cyclic octadecapeptides with potent activity against certain Grampositive bacteria and at least three major viral pathogens - H1V- 1, HSV-2, and influenza A. Specific Aims: This proposal is based on the recent discovery that low concentrations of retrocyclins and other theta-defensins can kill B. anthracis cells, prevent B. anthracis spores from germinating successfully, inactivate anthrax lethal factor(LF) and protect cefis from being killed by anthrax lethal toxin, a mixture of LF and protective antigen (PA). Our specific aims are: 1) to test e-defensins and structurally related cyclic octadecapeptides in vivo in murine models to ascertain their pharmacokinetic properties and potential toxicity; 2) to precisely define the molecular mechanisms responsible for their antimicrobial and antitoxic properties; 3) to design, synthesize and study new retrocyclin analogs in vitro, in vivo and in silico. Rationale: a-Defensins (HNPs) are naturally occurring peptide antibiotics that participate in the host defense activities of human neutrophils. 8-defensins are smaller peptide antibiotics that are produced by the leukocytes of monkeys, but not those of humans or chimps. In vitro, 8-defensins are broad-spectrum viral entry inhibitors, are effective against vancomycin-resistant enterococci (VRE), and appear to be highly promising agents to protect against infections initiated by B. anthracis spores. Methods: We will use in vitro, in viva, and computational methods to design, synthesize, and test retrocyclinlike cyclic octadecapeptides and to identify the most promising candidates for future development. Health relatedness and Lay language summary: New agents are urgently needed for key bioterrorism threats, such as anthrax. They are also needed for looming "natural" threats, such as influenza A, and for the growing number of antibiotic-resistant bacteria, such as VRE. This proposal is specifically directed towards B. anthracis, but its implications encompass many other urgent and unmet biomedical needs as well. Note: :The only change from the original proposal is the deletion of a single word (effectiveness) in Specific Aim 1, since we will not be performing in vivo tests with live virulent B.anthracis spores in mouse models as per the revised Specific Aims. All remaining Aims can be addressed in a two-year time period. PHS