A New Class of Allosteric HIV-1 Integrase Inhibitors Identified by Crystallographic Fragment Screening of the Catalytic Core Domain

Patel, Disha; Antwi, Janet; Koneru, Pratibha C.; Serrao, Erik; Forli, Stefano; Kessl, Jacques J.; Feng, Lei; Deng, Nanjie; Levy, Ronald M.; Fuchs, James R.; Olson, Arthur J.; Engelman, Alan; Bauman, J.D.; Kvaratskhelia, Mamuka; Arnold, Eddy

doi:10.1074/jbc.m116.753384

Cited by 22 publications

(23 citation statements)

References 63 publications

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“…Clinical mutations were found not only at the direct drug-binding sites but also non-functional regions [79], the latter of which can have indirect effects on drug resistance such as allosteric communication to the catalytic sites. The inhibition of such communication can be explored for novel classes of drugs, such as in the case of reverse transcriptase inhibitors (RTIs) [80], integrase inhibitors [81], and protease inhibitors (PIs) [82]. The non-nucleoside RTIs bind non-competitively to an allosteric site on p66 subunit to cause structural changes in the RT polymerase active site, hindering DNA polymerization.…”

Section: Analysis Of Allosteric Communicationmentioning

confidence: 99%

“…Our ongoing study has found further potential interferences targeting the p51 to affect overall RT activity [83]. On integrase, allosteric inhibitors impair the binding of integrase and the cellular cofactor LEDGF/p75 during HIV-1 replication to induce aberrant integrase multimerization [81]. Similarly, a potential allosteric protease inhibitor was found to bind to a site at the protease flap to equipotently inhibit both wild-type and certain drug-resistant variants [82].…”

Section: Analysis Of Allosteric Communicationmentioning

confidence: 99%

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The Determination of HIV-1 RT Mutation Rate, Its Possible Allosteric Effects, and Its Implications on Drug Resistance

Yeo

Goh

et al. 2020

Viruses

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The high mutation rate of the human immunodeficiency virus type 1 (HIV-1) plays a major role in treatment resistance, from the development of vaccines to therapeutic drugs. In addressing the crux of the issue, various attempts to estimate the mutation rate of HIV-1 resulted in a large range of 10−5–10−3 errors/bp/cycle due to the use of different types of investigation methods. In this review, we discuss the different assay methods, their findings on the mutation rates of HIV-1 and how the locations of mutations can be further analyzed for their allosteric effects to allow for new inhibitor designs. Given that HIV is one of the fastest mutating viruses, it serves as a good model for the comprehensive study of viral mutations that can give rise to a more horizontal understanding towards overall viral drug resistance as well as emerging viral diseases.

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Section: Analysis Of Allosteric Communicationmentioning

confidence: 99%

Section: Analysis Of Allosteric Communicationmentioning

confidence: 99%

The Determination of HIV-1 RT Mutation Rate, Its Possible Allosteric Effects, and Its Implications on Drug Resistance

Yeo

Goh

et al. 2020

Viruses

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“…Allosteric effects can underlie both drug resistance and inhibition mechanisms that can be explored for novel classes of drugs to develop novel classes of reverse transcriptase inhibitors (RTIs) [81], integrase inhibitors [82], and protease inhibitors (PIs) [83]. For example, non-nucleoside RTIs are known to bind non-competitively to an allosteric site on p66 subunit to cause structural changes to the RT polymerase active site, hindering DNA polymerization.…”

Section: Emerging Drug Resistance Mutations Considered As Allosteric mentioning

confidence: 99%

“…Studies suggested the RT p51 subunit, in addition to p66, to be also involved in allosteric couplings upon inhibitor binding [81,84]. Allosteric integrase inhibitors can impair the binding of integrase and the cellular cofactor LEDGF/p75 during HIV-1 replication and induce aberrant integrase multimerization [82]. Similarly, a potential allosteric modulator of HIV-1 protease was found to bind to an allosteric site at the protease flaps and equipotently inhibit both wild-type and certain drug resistant variants [83].…”

Section: Emerging Drug Resistance Mutations Considered As Allosteric mentioning

confidence: 99%

The Determination of HIV-1 RT Mutation Rate, Its Possible Allosteric Effects, and Its Implications on Drug Resistance

Yeo

Goh

et al. 2020

Preprint

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The high mutation rate of human immunodeficiency virus type 1 (HIV-1) plays a major role in treatment resistance from the development of vaccines to long-lasting drugs. In addressing the crux of the issue, various attempts to estimate the mutation rate of HIV-1 resulted in a large range of 10-5 - 10-3 errors/bp/cycle due to the use of different types of investigation methods. In this review, we discuss the different assay methods, their findings on the mutation rates of HIV-1 and how the location of these mutations can be further analyzed for their potential allosteric effects to reveal potentially new inhibitors with different pharmacodynamics that can be used to circumvent fast occurring HIV drug resistance. Given that HIV is one of the fastest mutating viruses, it is a good model for comprehensive study of its mutations that can give rise to much horizontal understanding towards overall viral drug resistance as well as emerging viral diseases.

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“…IN strand transfer inhibitors (INSTIs) 3 – 6 , together with allosteric inhibitors of IN 7 – 13 , efficiently inhibit viral replication. Allosteric inhibitors correspond to noncatalytic site inhibitors of IN and may interfere with distinct steps than integration, whereas INSTIs target the active site of IN and consistently inhibit the overall integration process by specifically blocking the ST reaction.…”

Section: Introductionmentioning

confidence: 99%

Probing Resistance Mutations in Retroviral Integrases by Direct Measurement of Dolutegravir Fluorescence

Thierry¹,

Lebourgeois²,

Simon³

et al. 2017

Sci Rep

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FDA-approved integrase strand transfer inhibitors (raltegravir, elvitegravir and dolutegravir) efficiently inhibit HIV-1 replication. Here, we present fluorescence properties of these inhibitors. Dolutegravir displays an excitation mode particularly dependent on Mg2+ chelation, allowing to directly probe its Mg2+-dependent binding to the prototype foamy virus (PFV) integrase. Dolutegravir-binding studied by both its fluorescence anisotropy and subsequent emission enhancement, strictly requires a preformed integrase/DNA complex, the ten terminal base pairs from the 3′-end of the DNA reactive strand being crucial to optimize dolutegravir-binding in the context of the ternary complex. From the protein side, mutation of any catalytic residue fully abolishes dolutegravir-binding. We also compared dolutegravir-binding to PFV F190Y, G187R and S217K mutants, corresponding to HIV-1 F121Y, G118R and G140S/Q148K mutations that confer low-to-high resistance levels against raltegravir/dolutegravir. The dolutegravir-binding properties derived from fluorescence-based binding assays and drug susceptibilities in terms of catalytic activity, are well correlated. Indeed, dolutegravir-binding to wild-type and F190Y integrases are comparable while strongly compromised with G187R and S217K. Accordingly, the two latter mutants are highly resistant to dolutegravir while F190Y shows only moderate or no resistance. Intrinsic fluorescence properties of dolutegravir are thus particularly suitable for a thorough characterization of both DNA-binding properties of integrase and resistance mutations.

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A New Class of Allosteric HIV-1 Integrase Inhibitors Identified by Crystallographic Fragment Screening of the Catalytic Core Domain

Abstract: Edited by Norma Allewell HIV-1 integrase (IN) is essential for virus replication andCollectively, our findings provide a plausible path for structurebased development of second-generation ALLINIs.

Cited by 22 publications

References 63 publications

The Determination of HIV-1 RT Mutation Rate, Its Possible Allosteric Effects, and Its Implications on Drug Resistance

The Determination of HIV-1 RT Mutation Rate, Its Possible Allosteric Effects, and Its Implications on Drug Resistance

The Determination of HIV-1 RT Mutation Rate, Its Possible Allosteric Effects, and Its Implications on Drug Resistance

Probing Resistance Mutations in Retroviral Integrases by Direct Measurement of Dolutegravir Fluorescence

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