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Albany 2013: Book of Abstracts

category image Albany 2013
Conversation 18
June 11-15 2013
©Adenine Press (2012)

Potent inhibition of HIV replication by RNA-binding peptide mimetics with unprecedented specificity

RNA provides an inviting target for pharmaceutical intervention in both infectious and chronic diseases, but it has so far been impossible to identify drug-like molecules with sufficient potency to lead to successful clinical applications. We have developed a new class of structurally constrained cyclic peptides to target the interaction between the human immunodeficiency virus (HIV-1) transactivator protein Tat and its response element TAR (Davidson et al. 2009; 2011), which plays an essential role in viral replication. Many previous attempts to inhibit this interaction have failed to yield molecules with sufficient potency and specificity to warrant pharmaceutical development. The peptidic mimics of Tat that are pM inhibitors of the Tat-TAR interaction and discriminate >1,000 fold between even closely related RNAs. They are potent inhibitors of viral replication (tens of nM) with no cytotoxicity and efficient cell penetration which specifically inhibit TAR-dependent reverse transcription as well as activation of transcription, and repress replication of a wide variety of viral strains representing all the major HIV clades in primary human lymphocytes (Lalonde et al. 2011). The potency and selectivity observed for this family of peptides is unprecedented among Tat inhibitors and suggest that peptides of this class may be more widely useful for the pharmacological inhibition of other protein-RNA interactions.

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References

    Davidson, A., Leeper, T.C., Athanassiou, Z., Patora-Komisarska, K., Karn, J., Robinson, J.A. and Varani, G. (2009) Simultaneous recognition of HIV-1 TAR RNA bulge and loop sequences by cyclic peptide mimics of Tat protein Proc. Natl. Acad. Sci. USA 106, 11931-11936.

    Davidson, A., Patora-Komisarska, K., Robinson, J.A. and Varani, G. (2011) Essential structural requirements for specific recognition of HIV TAR RNA by peptide mimetics of Tat protein. Nucleic Acids Research, 39, 248-256.

    Lalonde, M.S., Lobritz, M.A., Ratcliff, A., Chamanian, M., Athanassiou, Z., Tyagi, M., J., W., Robinson, J.A., Karn, J., Varani, G. et al. (2011) Inhibition of both HIV-1 reverse transcription and gene expression by a cyclic peptide tht binds the Tat-Transactivation response element (TAR) RNA. PLoS pathogens, 7, e1002038.


Gabriele Varani

Department of Biochemistry and Department of Chemistry
University of Washington
Seattle WA 98195-1700 Ph (206) 543 7113
varani@chem.washington.edu