Inhibiting the HIV Integration Process: Past, Present, and the Future

Abstract

HIV integrase (IN) catalyzes the insertion into the genome of the infected human cell of viral DNA produced by the retrotranscription process. The discovery of raltegravir validated the existence of the IN, which is a new target in the field of anti-HIV drug research. The mechanism of catalysis of IN is depicted, and the characteristics of the inhibitors of the catalytic site of this viral enzyme are reported. The role played by the resistance is elucidated, as well as the possibility of bypassing this problem. New approaches to block the integration process are depicted as future perspectives, such as development of allosteric IN inhibitors, dual inhibitors targeting both IN and other enzymes, inhibitors of enzymes that activate IN, activators of IN activity, as well as a gene therapy approach.

Detection of secondary binding sites in proteins using fragment screening

“…Indeed, given the significant size of most proteins it could be argued that it would be inefficient for evolution not to have resulted in multiple binding sites that could be used to regulate function. Furthermore, drug molecules that target such sites can offer an orthogonal mechanism for modulating the biological activity of a target protein and may have improved selectivity (5-7) and resistance profiles (8,9). The different mechanisms by which orthosteric and allosteric inhibitors operate also provide different opportunities (and pitfalls) for drug development (10).…”

Rous Sarcoma Virus Synaptic Complex Capable of Concerted Integration Is Kinetically Trapped by Human Immunodeficiency Virus Integrase Strand Transfer Inhibitors

“…Strand transfer inhibitors (STIs) directed against HIV IN are effective inhibitors in combination with other anti-retroviral drugs to prevent HIV replication in humans (17). Three IN STIs, raltegravir (RAL), elvitegravir (EVG), and dolutegravir (DTG), have been approved by the Food and Drug Administration for HIV treatment.…”

Multifunctional facets of retrovirus integrase

“…Thus, like with RT and protease inhibitors, the use of IN STIs has resulted in the emergence of drug-resistant viral strains that causes a loss of drug effectiveness. Both RAL and EVG possess a low genetic barrier giving rise to drug-resistant IN mutants (G140S/Q148H, N155S, Q148K, F121Y, T66I/S153Y) in tissue culture as well as in treated patients [72,83] . In contrast, DTG has a high genetic barrier and to date significant resistant IN mutants have been nearly absent in treatmentnaïve patients [81,84,85] .…”

“…A recent book [70] and several reviews of HIV IN inhibitors provide an extensive overview of the discovery of STIs and their mechanisms [47,[71][72][73] .…”