Sheathing the Hybrid Cleaver: Exploring Substrate‐Envelope‐Guided Drug Design with HIV‐1 RNase H

Abstract

Since the start if the epidemic in 1981, nearly 75 million people have been infected with the Human Immunodeficiency Virus (HIV). Despite significant medical advancements scientist have yet to find a cure for the disease and its subtypes. Many patients are treated with the FDA approved HAART (highly active antiretroviral therapy), in which several antiretroviral are given in attempt to control HIV reproduction and its quickly mutating enzymes. The advanced adaptability of the virus emphasizes the need for novel approaches to be taken to develop antivirals that are more robust in preventing drug resistance. We sought to investigate the strategies of substrate‐envelope‐guided design by studying variants of HIV‐1 RNase H. RNase H is an endonuclease that cleaves RNA from the RNA/DNA hybrids formed during reverse transcription of the viral genome. The approach taken to complete this study included considering RNase H structure, function, and mechanism. Variants were categorized and mapped to the structure of the enzyme. Resistance variants that extended beyond the substrate envelope were excluded in developing the proposed substrate envelope to target for inhibitor design. Applying the substrate‐envelope hypothesis developed by Dr. Cynthia Schiffer’s lab group afforded consideration of the method, while acquiring an advanced understanding of the structure and function of this significant domain within the larger, complex reverse transcription enzyme of HIV. Furthermore, RNase H active site serves as an emerging target of next generation therapeutic targets for treatments of HIV. Studying the evolutionary dynamics of this adaptive virus should be considered for the rational design of potent inhibitors of this protein, significant to HIV reproduction.Support or Funding InformationThe CREST Project is funded by NSF‐DUE 1022793 and NSF‐DUE 1323414.