Poster abstracts

Poster number 46 submitted by Jeff Joyner

Targeting the HIV-1 mRNA rev response element for modification using metallopeptides

Jeff C. Joyner (Ohio State Biochemistry Program, The Ohio State University), James A. Cowan (Department of Chemistry, The Ohio State University)

Abstract:
Compared to drugs whose mechanism is simple binding to a biological target, multiple-turnover compounds have potential for much higher efficacy and the ability to harness natural settings. We recently demonstrated catalytic targeting and transformation of a truncated version of the structured Rev response element (RRE) of HIV-1 mRNA by a class of Arg-rich peptides which form extremely stable square planar complexes with Cu(II) and Ni(II) cations via an amino-terminal Cu and Ni (ATCUN) binding motif and bind the RRE with nanomolar affinity via a Rev-like recognition sequence. If the RRE is cleaved efficiently in an HIV infected helper T-cell, HIV proliferation may be suppressed by prevention of translation of the viral Env coding region, required for HIV virion infectivity. Under oxidative conditions, catalytic modification of a truncated RRE target by Cu-peptide complexes has been demonstrated, presumably via the production of reactive oxygen species, which act in a distance dependent manner with highest effect nearest to the Cu center of ROS generation. In this manner, the redox settings of the cell interior may be harnessed to cause catalytic degradation of a targeted mRNA. The anti-cancer compound bleomycin is believed to degrade DNA in a similar fashion. The multiple-turnover metal-ATCUN-Rev complexes and their derivatives have potential as therapeutic anti-HIV compounds.

Keywords: RNA, metallopeptide, multiple turnover