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HIV-1 Integrase Strand Transfer Inhibitorswith Reduced Susceptibility to Drug Resistant Mutant Integrases

View Article: PubMed Central - PubMed

ABSTRACT

HIVintegrase (IN) strand transfer inhibitors (INSTIs) are amongthe newest anti-AIDS drugs; however, mutant forms of IN can conferresistance. We developed noncytotoxic naphthyridine-containing INSTIsthat retain low nanomolar IC50 values against HIV-1 variantsharboring all of the major INSTI-resistant mutations. We found byanalyzing crystal structures of inhibitors bound to the IN from theprototype foamy virus (PFV) that the most successful inhibitors showstriking mimicry of the bound viral DNA prior to 3′-processingand the bound host DNA prior to strand transfer. Using this conceptof “bi-substrate mimicry,” we developed a new broadlyeffective inhibitor that not only mimics aspects of both the boundtarget and viral DNA but also more completely fills the space theywould normally occupy. Maximizing shape complementarity and recapitulatingstructural components encompassing both of the IN DNA substrates couldserve as a guiding principle for the development of new INSTIs.

No MeSH data available.


Structures of the FDA-approved INSTIs(RAL, 1; EVG, 2; and DTG, 3) and heterobicyclic compounds ofthe current series (4). Colors highlight key functionalfeatures: metal-chelating triad of heteroatoms (red), halobenzyl rings(blue). The terminal ring of DTG and the corresponding 6-substituentsdescribed in the present work shown in green shading.
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fig1: Structures of the FDA-approved INSTIs(RAL, 1; EVG, 2; and DTG, 3) and heterobicyclic compounds ofthe current series (4). Colors highlight key functionalfeatures: metal-chelating triad of heteroatoms (red), halobenzyl rings(blue). The terminal ring of DTG and the corresponding 6-substituentsdescribed in the present work shown in green shading.

Mentions: INSTIs selectively bind at the interfaceof IN and the viral DNA end following its 3′-P.18,19,25 INSTIs containa triad of heteroatoms (shown in red in Figure 1) that chelate the essential pair of Mg2+ ions in the IN active site. INSTIs also typically includea halobenzyl ring that stacks against the base of the penultimatedeoxycytidine near the processed 3′-end of the viral DNA (shownin blue in Figure 1).3,26 Our long-term goal is to develop small moleculesthat are active against IN mutants that are resistant to current INSTIs.Initially, our efforts were directed at the retention of efficacyagainst the Y143R and N155H mutants and the double mutant, Q148H/G140S.13−16 While these are associated with clinical HIV-1 resistance to RAL,there is a considerable overlap in the resistance profiles of RALand EVG.27,28 Prior to the current work, we had performedextensive investigations on a core 1-hydroxy-2-oxo-1,8-naphthyridineplatform.23,24 These efforts yielded compound 4a, with a ST inhibitory value of IC50 = 19 nM in an in vitro IN assay (compound 4a, Table 1) and an antiviral potency equivalentto RAL (EC50 ≃ 1 nM) against HIV vectors carryingwild-type (WT) IN in single-round replication assays (Table 2). In similar assays, RAL showsa significant loss of antiviral efficacy when the HIV-1 vectors employedcarried the drug resistance mutations Y143R, N155H, or Q148H/G140Smutants (EC50 ≃ 160 nM, 150 nM, and 1900 nM, respectively).In contrast, 4a shows effective retention of antiviralpotency against both the Y143R and N155H variants (EC50 ≃ 2 nM and 5 nM, respectively, Table 2).24 These valuesare similar to those displayed by DTG; however, DTG is more potentthan 4a against the Q148H/G140S double mutant (4a EC50 ≃ 35 nM; DTG EC50 ≃6 nM).24


HIV-1 Integrase Strand Transfer Inhibitorswith Reduced Susceptibility to Drug Resistant Mutant Integrases
Structures of the FDA-approved INSTIs(RAL, 1; EVG, 2; and DTG, 3) and heterobicyclic compounds ofthe current series (4). Colors highlight key functionalfeatures: metal-chelating triad of heteroatoms (red), halobenzyl rings(blue). The terminal ring of DTG and the corresponding 6-substituentsdescribed in the present work shown in green shading.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4836387&req=5

fig1: Structures of the FDA-approved INSTIs(RAL, 1; EVG, 2; and DTG, 3) and heterobicyclic compounds ofthe current series (4). Colors highlight key functionalfeatures: metal-chelating triad of heteroatoms (red), halobenzyl rings(blue). The terminal ring of DTG and the corresponding 6-substituentsdescribed in the present work shown in green shading.
Mentions: INSTIs selectively bind at the interfaceof IN and the viral DNA end following its 3′-P.18,19,25 INSTIs containa triad of heteroatoms (shown in red in Figure 1) that chelate the essential pair of Mg2+ ions in the IN active site. INSTIs also typically includea halobenzyl ring that stacks against the base of the penultimatedeoxycytidine near the processed 3′-end of the viral DNA (shownin blue in Figure 1).3,26 Our long-term goal is to develop small moleculesthat are active against IN mutants that are resistant to current INSTIs.Initially, our efforts were directed at the retention of efficacyagainst the Y143R and N155H mutants and the double mutant, Q148H/G140S.13−16 While these are associated with clinical HIV-1 resistance to RAL,there is a considerable overlap in the resistance profiles of RALand EVG.27,28 Prior to the current work, we had performedextensive investigations on a core 1-hydroxy-2-oxo-1,8-naphthyridineplatform.23,24 These efforts yielded compound 4a, with a ST inhibitory value of IC50 = 19 nM in an in vitro IN assay (compound 4a, Table 1) and an antiviral potency equivalentto RAL (EC50 ≃ 1 nM) against HIV vectors carryingwild-type (WT) IN in single-round replication assays (Table 2). In similar assays, RAL showsa significant loss of antiviral efficacy when the HIV-1 vectors employedcarried the drug resistance mutations Y143R, N155H, or Q148H/G140Smutants (EC50 ≃ 160 nM, 150 nM, and 1900 nM, respectively).In contrast, 4a shows effective retention of antiviralpotency against both the Y143R and N155H variants (EC50 ≃ 2 nM and 5 nM, respectively, Table 2).24 These valuesare similar to those displayed by DTG; however, DTG is more potentthan 4a against the Q148H/G140S double mutant (4a EC50 ≃ 35 nM; DTG EC50 ≃6 nM).24

View Article: PubMed Central - PubMed

ABSTRACT

HIVintegrase (IN) strand transfer inhibitors (INSTIs) are amongthe newest anti-AIDS drugs; however, mutant forms of IN can conferresistance. We developed noncytotoxic naphthyridine-containing INSTIsthat retain low nanomolar IC50 values against HIV-1 variantsharboring all of the major INSTI-resistant mutations. We found byanalyzing crystal structures of inhibitors bound to the IN from theprototype foamy virus (PFV) that the most successful inhibitors showstriking mimicry of the bound viral DNA prior to 3′-processingand the bound host DNA prior to strand transfer. Using this conceptof “bi-substrate mimicry,” we developed a new broadlyeffective inhibitor that not only mimics aspects of both the boundtarget and viral DNA but also more completely fills the space theywould normally occupy. Maximizing shape complementarity and recapitulatingstructural components encompassing both of the IN DNA substrates couldserve as a guiding principle for the development of new INSTIs.

No MeSH data available.