The Drug-Induced Interface That Drives HIV-1 Integrase Hypermultimerization and Loss of Function

Singer, Matthew R; Dinh, Tung; Levintov, Lev; Annamalai, Arun S.; Rey, Juan S.; Briganti, Lorenzo; Cook, Nicola; Pye, V.E.; Taylor, Ian A.; Kim, Kyungjin; Engelman, Alan; Kim, Baek; Perilla, Juan R.; Kvaratskhelia, Mamuka; Cherepanov, Peter

doi:10.1128/mbio.03560-22

Cited by 6 publications

(27 citation statements)

References 96 publications

(173 reference statements)

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“…4). Therefore, to understand how Y99H/A128T mutations affect the CTD binding, we superimposed our crystal structure of CCD Y99H/A128 + PIR onto the recently reported structure of the CTD-CCD + PIR (32) (Fig. 5B,C, Fig.…”

Section: Resultsmentioning

confidence: 99%

“…5B and Fig. S4A show optimal positioning of CCD residues Thr124 and Ala128 with respect to CTD residues Tyr226 and Ile268 at the WT CCD-PIR-CTD interface (32).…”

Section: Resultsmentioning

confidence: 99%

“…Recently, two-domain HIV-1 IN CTD-CCD constructs were developed to study ALLINI-induced CTD-CCD interaction (32). Our efforts to obtain a crystal structure for the CTD-CCD Y99H/A128T + PIR complex have not been successful likely due to the inability of CTD to bind to the CCD Y99H/A128T + PIR complex (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Upon binding to the V-shaped cavity at the CCD dimer interface, ALLINIs act as molecular glues to recruit CTD (31)(32)(33). Therefore, we tested how Y99H/A128T IN mutations affected formation of the CCD-PIR-CTD complex.…”

Section: Biochemical Mechanisms Of the Iny99h/a128t Resistance To Pirmentioning

confidence: 99%

“…The invariant CTD residues engage with both CCD and the inhibitor to stabilize the CCD-ALLINI-CTD interface. Because ALLINIs are sandwiched between CCD and CTD, these inhibitors exhibit a substantially lower K off rate and a higher affinity ( K D ) for the CCD-ALLINI-CTD vs CCD-ALLINI complex (32).…”

Section: Introductionmentioning

confidence: 99%

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The structural and mechanistic bases for the viral resistance to allosteric HIV-1 integrase inhibitor pirmitegravir

Dinh,

Tber,

Rey

et al. 2024

Preprint

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Allosteric HIV-1 integrase (IN) inhibitors (ALLINIs) are investigational antiretroviral agents which potently impair virion maturation by inducing hyper-multimerization of IN and inhibiting its interaction with viral genomic RNA. The pyrrolopyridine-based ALLINI pirmitegravir (PIR) has recently advanced into Phase 2a clinical trials. Previous cell culture based viral breakthrough assays identified the HIV-1(Y99H/A128T IN) variant that confers substantial resistance to this inhibitor. Here, we have elucidated the unexpected mechanism of viral resistance to PIR. While both Tyr99 and Ala128 are positioned within the inhibitor binding V-shaped cavity at the IN catalytic core domain (CCD) dimer interface, the Y99H/A128T IN mutations did not substantially affect direct binding of PIR to the CCD dimer or functional oligomerization of full-length IN. Instead, the drug-resistant mutations introduced a steric hindrance at the inhibitor mediated interface between CCD and C-terminal domain (CTD) and compromised CTD binding to the CCDY99H/A128T + PIR complex. Consequently, full-length INY99H/A128T was substantially less susceptible to the PIR induced hyper-multimerization than the WT protein, and HIV-1(Y99H/A128T IN) conferred >150-fold resistance to the inhibitor compared to the WT virus. By rationally modifying PIR we have developed its analog EKC110, which readily induced hyper-multimerization of INY99H/A128T in vitro and was ~14-fold more potent against HIV-1(Y99H/A128T IN) than the parent inhibitor. These findings suggest a path for developing improved PIR chemotypes with a higher barrier to resistance for their potential clinical use.

show abstract

Section: Resultsmentioning

confidence: 99%

“…5B and Fig. S4A show optimal positioning of CCD residues Thr124 and Ala128 with respect to CTD residues Tyr226 and Ile268 at the WT CCD-PIR-CTD interface (32).…”

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Biochemical Mechanisms Of the Iny99h/a128t Resistance To Pirmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

The structural and mechanistic bases for the viral resistance to allosteric HIV-1 integrase inhibitor pirmitegravir

Dinh,

Tber,

Rey

et al. 2024

Preprint

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Quinolinonyl Derivatives as Dual Inhibitors of the HIV-1 Integrase Catalytic Site and Integrase–RNA interactions

Patacchini,

Madia,

Albano

et al. 2024

ACS Med. Chem. Lett.

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The HIV-1 integrase (IN) plays a critical role in the viral lifecycle by integrating the viral DNA into the host chromosome. The catalytic function of IN has been exploited as a target, with five drugs acting as active site binders (IN strand transfer inhibitors, INSTIs). However, IN mutations conferring low-level resistance to INSTIs have been reported. Therefore, new IN inhibitors with different mechanisms of action are needed. The allosteric inhibition of IN, exerted by allosteric IN inhibitors (ALLINIs), is gaining interest. ALLINIs inhibit IN by inducing aberrant IN multimerization with different mechanisms. Furthermore, recent discoveries unveiled that IN has an under-studied yet equally vital second function. This involves IN binding to the RNA genome in virions, necessary for proper virion maturation. In this work, we describe a series of quinolinonyl derivatives as inhibitors of both the IN catalytic functions and IN−RNA interactions, which impair both early and late steps of viral replication.

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Biological and Structural Analyses of New Potent Allosteric Inhibitors of HIV-1 Integrase

Bonnard¹,

Rouzic²,

Singer

et al. 2023

Antimicrob Agents Chemother

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The Drug-Induced Interface That Drives HIV-1 Integrase Hypermultimerization and Loss of Function

Cited by 6 publications

References 96 publications

The structural and mechanistic bases for the viral resistance to allosteric HIV-1 integrase inhibitor pirmitegravir

The structural and mechanistic bases for the viral resistance to allosteric HIV-1 integrase inhibitor pirmitegravir

Quinolinonyl Derivatives as Dual Inhibitors of the HIV-1 Integrase Catalytic Site and Integrase–RNA interactions

Biological and Structural Analyses of New Potent Allosteric Inhibitors of HIV-1 Integrase

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