Novel therapeutic strategies targeting HIV integrase

HIV integrase (IN) is pivotal in the viral replication cycle as it catalyzes the insertion of the reverse transcribed viral genome into host chromatin. Integrase catalyzes two distinct steps, 3' processing and strand transfer. During 3' processing, integrase excises a dinucleotide from the 3' terminus of viral cDNA. This 3'-processed viral DNA is then covalently linked to host DNA during strand transfer [1]. This unique process has always been considered a viable drug target, which several early studies attempted to exploit [2]. Early integrase inhibitors (INIs) included peptides [3,4], nucleotides [5] and DNA complexes [6] as well as small molecules derived either from natural products [5] or by rational drug design strategies [4,7]. Even though some of these compounds advanced into preclinical trials, further clinical development was always curtailed due to in vivo toxicity and/or non-specific off-target effects. More detailed reviews on the development of early INIs have been published [2,4,8].For any inhibitor to be considered useful as an antiviral in combination therapy for HIV, selectivity (such as for IN) that is distinct from effects on other targets (such as RT and protease) needs to be proven. The 4-aryl-2,4-diketobutanoic acid inhibitors containing a distinct diketo acid moiety (DKA) were identified in 2000 by Merck investigators from a screen of 250,000 compounds, and for a time were the only biologically validated INIs [9]. Their antiviral activity in cell culture was mitigated by the development of resistance mutations in the IN protein, thereby confirming their mode of action [9]. These compounds, exemplified by L-731988 [10], were found to inhibit strand transfer with much higher potency (half-inhibitory concentration (IC50) = 80 nM) than 3' prime processing (6 μM) [9], and they were thus referred to as integrase strand transfer inhibitors (INSTIs). IN, like most nucleotidyltransferase enzymes, requires two divalent cations bound at the active site