The HIV-1 Reverse Transcription (RT) Process as Target for RT Inhibitors

Abstract

Since the Human Immunodeficiency Virus Type 1 (HIV‐1) was identified as the etiologic agent of the Acquired Immune Deficiency Syndrome (AIDS), the HIV‐1 reverse transcriptase (RT) has been the subject of intensive study. The reverse transcription entails the transition of the single‐stranded viral RNA into double‐stranded proviral DNA, which is then integrated into the host chromosome. Therefore, the HIV‐1 reverse transcriptase plays a pivotal role in the life cycle of the virus and is consequently an interesting target for anti‐HIV drug therapy. In the first section, we describe the complex process of reverse transcription and the different activities involved in this process. We then highlight the structure‐function relationship of the HIV‐1 reverse transcriptase, which is of great importance for a better understanding of resistance development, a major problem in anti‐AIDS therapies. Finally, we summarize the mechanisms of HIV resistance toward various RT inhibitors and the implications thereof for the current anti‐HIV drug therapies. © 2000 John Wiley & Sons, Inc. Med Res Rev, 20, No. 2, 129–154, 2000

Poliovirus RNA-Dependent RNA Polymerase (3Dpol): Pre-Steady-State Kinetic Analysis of Ribonucleotide Incorporation in the Presence of Mg2+

“…Time courses at fixed nucleotide concentration were fit to (1) where A is the amplitude of the burst, k obs is the observed first-order rate constant describing the burst, t is the time, and C is a constant. The apparent binding constant (K d,app ) and maximal rate constant for nucleotide incorporation (k pol ) were determined using the equation: (2) The pulse-quench data were fit to an equation describing a two-step, irreversible process: (3) where A is the amplitude of the burst, k 1 is the rate constant for the first phase, k 2 is the rate constant for the second phase, and t is the time.…”

The Stereoselective Targeting of a Specific Enzyme-Substrate Complex Is the Molecular Mechanism for the Synergic Inhibition of HIV-1 Reverse Transcriptase by (R)-(−)-PPO464

“…where (D 50 (1) represents the dose of agent 1 required to produce 50% effect alone, and (D) 1 is the dose of that agent required to produce the same 50% effect in combination with (D) 2 . Similarly, (D 50 (2) is the dose of agent 2 required to produce the same 50% effect alone, and (D) 2 is the dose required to produce the same effect in combination.…”

“…The virus-encoded HIV-1 1 reverse transcriptase (RT) is essential for the viral replication cycle and therefore represents a logical target for antiviral chemotherapy (1,2). Recently, a class of inhibitors targeted to the viral RT, the so-called NNRTIs, have gained a definitive place in the treatment of HIV-1 infections along with NRTIs and PIs (3).…”

NMR-based identification of peptides that specifically recognize the d-arm of tRNA

“…Indeed, the 18 nucleotides at the 3' end of tRNALys3 are complementary to the primer binding site in the viral RNA (for reviews, see [17][18][19]). This tRNALys3-viral RNA duplex is then recognised by the reverse transcriptase (for reviews [17,20]) which can start the elongation of the minus DNA strand. In order to prevent the formation of the initiation complex (tRNALys3/viral RNA), an attractive strategy would be to isolate ligands that bind to tRNALys3 and that could then hinder its recruitment by viral factors : the nucleocapsid protein, the reverse transcriptase or the viral RNA.…”