Abstract
During the integration step, human immunodeficiency virus type 1 integrase (IN) interacts with viral DNA and the cellular cofactor LEDGF/p75 to effectively integrate the reverse transcript into the host chromatin. Allosteric human immunodeficiency virus type 1 integrase inhibitors (ALLINIs) are a new class of antiviral agents that bind at the dimer interface of the IN catalytic core domain and occupy the binding site of LEDGF/p75. While originally designed to block IN-LEDGF/p75 interactions during viral integration, several of these compounds have been shown to also severely impact viral maturation through an IN multimerization mechanism. In this study, we tested the hypothesis that these dual properties of ALLINIs could be decoupled toward late stage viral replication effects by generating additional contact points between the bound ALLINI and a third subunit of IN. By sequential derivatization at position 7 of a quinoline-based ALLINI scaffold, we show that IN multimerization properties are enhanced by optimizing hydrophobic interactions between the compound and the C-terminal domain of the third IN subunit. These features not only improve the overall antiviral potencies of these compounds but also significantly shift the ALLINIs selectivity toward the viral maturation stage. Thus, we demonstrate that to fully maximize the potency of ALLINIs, the interactions between the inhibitor and all three IN subunits need to be simultaneously optimized.
Highlights
Bound to IN [3,4,5,6]
Through computer simulations [25], crystallography [26], and biochemical experiments [27, 28], it has been previously suggested that in addition to binding at the IN catalytic core domain (CCD) dimer interface, some Allosteric IN inhibitors (ALLINIs) could bridge with the C-terminal domain (CTD) of a third IN subunit (Fig. 1), a feature that could be important for the development of the antiviral potency of this class of inhibitors
The compounds belonging to the ALLINI class share several common structural features including a central aromatic scaffold which have been the subject of several substitution studies that have been able to modulate the potency of these molecules
Summary
Bound to IN [3,4,5,6]. Efficient integration of the HIV-1 genome in infected cells requires the interaction between IN and the cellular chromatin-associated protein LEDGF/p75 which acts as a bimodal tether to link the IN-vDNA complex to active genes [7,8,9,10,11,12]. Through computer simulations [25], crystallography [26], and biochemical experiments [27, 28], it has been previously suggested that in addition to binding at the IN CCD dimer interface, some ALLINIs could bridge with the CTD of a third IN subunit (Fig. 1), a feature that could be important for the development of the antiviral potency of this class of inhibitors.
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