Optimizing the Multimerization Properties of Quinoline-Based Allosteric HIV-1 Integrase Inhibitors

Abstract

Allosteric HIV-1 Integrase (IN) Inhibitors or ALLINIs bind at the dimer interface of the IN, away from the enzymatic catalytic site, and disable viral replication by inducing over-multimerization of IN. Interestingly, these inhibitors are capable of impacting both the early and late stages of viral replication. To better understand the important binding features of multi-substituted quinoline-based ALLINIs, we have surveyed published studies on IN multimerization and antiviral properties of various substituted quinolines at the 4, 6, 7, and 8 positions. Here we show how the efficacy of these inhibitors can be modulated by the nature of the substitutions at those positions. These features not only improve the overall antiviral potencies of these compounds but also significantly shift the selectivity toward the viral maturation stage. Thus, to fully maximize the potency of ALLINIs, the interactions between the inhibitor and multiple IN subunits need to be simultaneously optimized.

Keywords: ALLINI; HIV; aberrant integrase multimerization; allosteric integrase inhibitor; integrase; quinoline; virus maturation.

Figure 1

Quilonine-based inhibitors of IN-LEDGF/p75 interaction.

Figure 2

Crystal structure of quinoline 3 bound to IN CCD (pdb 3LPU).

Figure 3

Quinoline-based inhibitors of 3P activity.

Figure 4

FRET-based IN multimerization in vitro assay.

Figure 5

ALLINI binding features. ALLINI binding pocket (A) and IN subunit crystallographic arrangement (B). The IN subunits 1, 2, and 3 are color-coded green, yellow, and magenta, respectively (pdb 5HOT).

Figure 6

BI 224436.

Figure 7

Binding model of compound 66.