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Human Immunodeficiency Virus-1 Reverse Transcriptase

Introduction

The retrovirus human immunodeficiency virus (HIV) is a subsequent progression to acquired immune deficiency syndrome (AIDS). This disease is a continuous worldwide epidemic. The protein HIV-1 reverse transcriptase is one of the key players in the mechanism of infections by this retrovirus. The protein HIV-I reverse transcriptase is the enzyme that’s main responsibility is to copy a single-stranded viral RNA genome into a double stranded DNA.^[1]In turn the newly developed DNA can then be incorporated into the host cell genome. The HIV-1 reverse transcriptase enzyme has two domains within its structure. The two domains are a DNA polymerase domain and ribonuclease H (also called RNase H) domain. The role of the DNA polymerase is to copy either RNA or DNA template strands. The purpose of the ribonuclease H is to cleave the RNA duplex after the DNA synthesis has occurred so that the newly created DNA can generate a second strand.^[2]

Structure

Mechanism

HIV-RT is a multifunctional enzyme, possessing three separate activities. The first being the RNA dependent polymerase(RDDP) where the enzyme makes a single strand copy of DNA using the viral RNA as the template strand. With the completion of the RDDP step a RNA-DNA duplex is formed and it is at this stage the RNase H domain of the enzyme facilitates RNA release from the cDNA strand. Once the cDNA has been released the enzyme enters its DNA dependent DNA polymerase(DDDP) activity. During this phase, the double strand DNA copy of the viral genome is completed and is ready for incorporation into the host cells DNA.

Inhibition and Drug Design

The reverse transcriptase enzyme is on of several targets for inhibition in the effort to fight HIV infection. Inhibitors for HIV RT can be grouped into two distinct classes; nucleotide RT inhibitors (NRTIs) and non-nucleotide RT inhibitors (NNRTIs). NRTIs function through competitive inhibition mechanism. These molecules are phosphorylated by cellular kinases and as a result mimic the structure of nucleotides. However, unlike actual nucleotides, NRTIs do not posses the 3'-OH group and as a result terminate chain elongation once they are incorporated into the DNA strand by the enzyme.

Non-nucleotide RT Inhibitors

NNRTI's are non-competitive inhibitors that bind to a specific site on the enzyme but not to the active site. These molecules are typically hydrophobic and bind to a hydrophobic pocket on RT that is in close proximity to the active site. There are some NNRTIs that have been found that do not follow this general scheme and bind to alternative locations on the enzyme, these locations vary with each inhibitor. NNRTIs are highly specific and rarely have any effect on more than one strain of HIV.

References

1. ↑ Herschhorn, Alon, Iris Oz-Gleenberg, and Amnon Hizi. "Mechanism of Inhibition of HIV-1 Reverse Transcriptase by the Novel Broad-Range DNA Polyermerase Inhibitor N-{2-[4-(Aminosulfonyl)phenyl]ethyl}-2-(2-thienyl)acetamide." Biochemistry 47(2008): 490-502.
2. ↑ Grohmann, Dina, Julien Godet, Yves Mely, Jean-Luc Darlix, and Tobias Restle. "HIV-1 Nucleocapsid Traps Reverse Transcriptase on Nucleic Acid Substrates." Biochemistry 47(2008): 12230-12240