Currently, used antiretroviral HIV therapy drugs exclusively target critical groups in the
enzymes essential for the viral life cycle. Increased mutagenesis of their genes changes these viral
enzymes, which once mutated can evade therapeutic targeting, effects which confer drug resistance.
To circumvent this, our review addresses a strategy to design and derive HIV-Integrase
(HIV-IN) inhibitors which simultaneously target two IN functional domains, rendering it inactive
even if the enzyme accumulates many mutations. First we review the enzymatic role of IN to insert
the copied viral DNA into a chromosome of the host T lymphocyte, highlighting its main functional
and structural features to be subjected to inhibitory action. From a functional and structural
perspective we present all classes of HIV-IN inhibitors with their most representative candidates.
For each chosen compound we also explain its mechanism of IN inhibition. We use the recently
resolved cryo EM IN tetramer intasome DNA complex onto which we dock various reference IN
inhibitory chemical scaffolds such as to target adjacent functional IN domains. Pairing compounds
with complementary activity, which dock in the vicinity of a IN structural microdomain, we design
bifunctional new drugs which may not only be more resilient to IN mutations but also may be
more potent inhibitors than their original counterparts. In the end of our review we propose synthesis
pathways to link such paired compounds with enhanced synergistic IN inhibitory effects.
Keywords: HIV, Integrase, RT, ART, LTR, NTD, CCD, CTD.
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