Abstract
Allosteric HIV-1 integrase (IN) inhibitors (ALLINIs) are a promising new class of antiretroviral agents that disrupt proper viral maturation by inducing hyper-multimerization of IN. Here we show that lead pyridine-based ALLINI KF116 exhibits striking selectivity for IN tetramers versus lower order protein oligomers. IN structural features that are essential for its functional tetramerization and HIV-1 replication are also critically important for KF116 mediated higher-order IN multimerization. Live cell imaging of single viral particles revealed that KF116 treatment during virion production compromises the tight association of IN with capsid cores during subsequent infection of target cells. We have synthesized the highly active (-)-KF116 enantiomer, which displayed EC50 of ~7 nM against wild type HIV-1 and ~10 fold higher, sub-nM activity against a clinically relevant dolutegravir resistant mutant virus suggesting potential clinical benefits for complementing dolutegravir therapy with pyridine-based ALLINIs.
Highlights
Multifunctional HIV-1 integrase (IN) is an important therapeutic target
To examine which of these forms are targeted by Allosteric HIV-1 integrase (IN) inhibitors (ALLINIs), we have separated different oligomeric forms of WT IN by size exclusion chromatography (SEC) (Figure 1B)
To prevent re-equilibration of separated species, equimolar concentrations of tetramers, dimers and monomers were immediately incubated with KF116 and formation of the inhibitor induced higher-order IN multimers were monitored by dynamic light scattering (DLS)
Summary
Multifunctional HIV-1 integrase (IN) is an important therapeutic target. HIV-1 IN strand transfer inhibitors (INSTIs), which have become a first-line therapy to treat HIV-1 infected patients, block the catalytic function of the viral protein during the early phase of infection and prevent integration of viral cDNA into human chromosomes (Hazuda, 2012; Hazuda et al, 2000; McColl and Chen, 2010). Varying the substituted groups have resulted in highly potent inhibitors such as BI224436 with antiviral EC50 of ~14 nM (Fader et al, 2014b) (Figure 1A); ii) other studies successfully explored different core ring structures (Demeulemeester et al, 2014; Fader et al, 2016; Patel et al, 2016a; Patel et al, 2016b; Sharma et al, 2014) to synthesize highly potent ALLINIs. We and others have rationally developed pyridine-based compounds that exhibit markedly improved antiviral activities and significantly enhanced genetic pressure for the evolution of resistance compared with archetypal quinoline-based compounds (Fader et al, 2016; Hoyte et al, 2017; Sharma et al, 2014). These findings suggest potential clinical benefits for combining KF116 and DTG therapies to limit HIV-1 options for developing drug resistant variants in patients
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