Despite advances made in its therapeutic management, human immunodeficiency virus (HIV) infection has remained an intractable problem, and complete eradication of the virus an unrealized goal. Experience in the clinical application of combination therapy using a variety of reverse transcriptase and protease inhibitors have revealed a number of challenges, in spite of the observed albeit temporary success in reduction of patient viral loads. Problems with current protocols include poor patient compliance, and the presence of latent reservoirs of virus that ultimately result in the appearance of phenotypic resistance. These considerations necessitate continued research and development into alternative strategies to circumvent the aforementioned problems. One approach to minimizing and/or eliminating the appearance of escape mutants and latent viral reservoirs is the targeting of essential and mutationally intolerant enzymes such as the nucleocapsid protein, which contains two highly conserved zinc knuckles. Concerns have been raised regarding the targeting of this protein, since the ubiquitous occurrence of important mammalian zinc finger proteins implies that drug specificity towards the nucleocapsid protein may be difficult to attain. In this review, strong evidence supporting the hypothesis that this protein can be targeted to the exclusion of other cellular zinc finger proteins is presented. The effects of small molecule induced abrogation of nucleocapsid protein mediated activities, as well as efforts to develop nucleocapsid protein inhibitors as antiretrovirals are also discussed.
Keywords: nucleocapsid, zinc knuckle, antiretrovirals, small molecule inhibitors, electrophiles
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