Structural basis of second-generation HIV integrase inhibitor action and viral resistance

Cook, Nicola; Li, Wen; Berta, Dénes; Badaoui, Magd; Ballandras-Colas, Allison; Nans, Andrea; Kotecha, Abhay; Rosta, Edina; Engelman, Alan; Cherepanov, Peter

doi:10.1126/science.aay4919

Cited by 83 publications

(214 citation statements)

References 64 publications

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“…In IN GSH, the N-terminal amino group is oriented toward the C-terminal end of the ɑ2 helix, whereas in IN 1F, it is flipped ~ 180° and oriented toward the ɑ3 helix of a neighboring NTD. The same NTD–NTD interface is observed in dodecameric HIV-1, hexadecameric MVV, and SIV intasome structures [ 22 – 25 ], and the NTDs modeled at this position adopt extended ɑ1 helical structures in four of six structures (Additional file 3 : Figure S3). The NTDs that do not form an NTD–NTD interface show a variety of structures: disordered, partially unstructured, and extended (Additional file 3 : Figure S3).…”

Section: Resultsmentioning

confidence: 61%

“…This NTD does not form NTD-NTD interactions in dodecameric or hexadecameric intasomes and shows a range of ɑ1 helical structures: disordered, partially unstructured, and extended [23]. Intasomes of a closely-related simian immunodeficiency virus were prepared with IN purified with an N-terminal affinity tag and subsequent human rhinovirus 3C protease cleavage, leaving 3 residues (G-P-G-) preceding F1 [22]. The NTDs in these structures show extended ɑ1 helices.…”

Section: H12cmentioning

confidence: 99%

“…IN carries out two catalytic reactions: 3′-processing and strand transfer [1], in a macromolecular complex consisting of multiple IN protomers, viral DNA, cofactors, and host cell proteins termed the intasome [14,[19][20][21][22][23][24][25]. Early intasome structures were determined with IN from the prototype foamy virus (PFV) [26][27][28][29][30], revealing the structural details of enzymatic activity and the mechanism of action of the strand-transfer inhibitors (STIs), which displace the 3′ viral DNA end from the active site, rendering the intasome nonfunctional [22,23,31,32]. STIs are in widespread clinical use [33], however, as with all antiretrovirals, development of resistance is a major barrier to durable inhibition of viral replication [34,35].…”

Section: Introductionmentioning

confidence: 99%

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Influence of the amino-terminal sequence on the structure and function of HIV integrase

et al. 2020

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Background: Antiretroviral therapy (ART) can mitigate the morbidity and mortality caused by the human immunodeficiency virus (HIV). Successful development of ART can be accelerated by accurate structural and biochemical data on targets and their responses to inhibitors. One important ART target, HIV integrase (IN), has historically been studied in vitro in a modified form adapted to bacterial overexpression, with a methionine or a longer fusion protein sequence at the N-terminus. In contrast, IN present in viral particles is produced by proteolytic cleavage of the Pol polyprotein, which leaves a phenylalanine at the N-terminus (IN 1F). Inspection of available structures suggested that added residues on the N-terminus might disrupt proper protein folding and formation of multimeric complexes. Results: We purified HIV-1 IN 1F 1-212 and solved its structure at 2.4 Å resolution, which showed extension of an N-terminal helix compared to the published structure of IN 1-212. Full-length IN 1F showed increased in vitro catalytic activity in assays of coupled joining of the two viral DNA ends compared to two IN variants containing additional N-terminal residues. IN 1F was also altered in its sensitivity to inhibitors, showing decreased sensitivity to the strandtransfer inhibitor raltegravir and increased sensitivity to allosteric integrase inhibitors. In solution, IN 1F exists as monomers and dimers, in contrast to other IN preparations which exist as higher-order oligomers. Conclusions: The structural, biochemical, and biophysical characterization of IN 1F reveals the conformation of the native HIV-1 IN N-terminus and accompanying unique biochemical and biophysical properties. IN 1F thus represents an improved reagent for use in integration reactions in vitro and the development of antiretroviral agents.

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Section: Resultsmentioning

confidence: 61%

Section: H12cmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Influence of the amino-terminal sequence on the structure and function of HIV integrase

et al. 2020

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“…And Bictegravir and Dolutegravir are integrase inhibitors used in combination with other drug for treatment of HIV infection. They are structurally related as the former is a derivation from the latter (75). And their binding energies to nsp5 are also very similar (-9.5 kcal/mol for Bictegravir and -8.9…”

Section: Drug Perform Well In Our Screening But Not Under Clinical Trialmentioning

confidence: 87%

Systemic in Silico Screening in Drug Discovery for Coronavirus Disease (COVID-19) with an Online Interactive Web Server

Xu¹,

Ke²,

Liu³

et al. 2020

Preprint

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<p>The emergence of the new coronavirus (nCoV-19) has brought global impact on human health, whilst the interaction between the virus and the host is the foundation of the disease. The viral genome codes a cluster of proteins, each with a unique function in the event of host invasion or viral development. Under current adverse situation, we employ virtual screening tools in searching for drugs and nature products which have been already deposited in the DrugBank in attempt to accelerate the drug discovery process. This study provides an initial evaluation of current drug candidates from various reports using our systemic in silico drug screening based on structures of viral proteins and human ACE2 receptor. Besides, we built an interactive online platform (<a href="https://shennongproject.com:11443/#/home">https://shennongproject.com:11443/#/home</a>) for browsing these results with the visual display of small molecule docked on its potential target protein, without installing any specialized structural software. With continuous maintenance and incorporation of data from laboratory works, it may serve not only as the assessment tool for the new drug discovery but also an educational website to meet general interest from the public.</p>

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“…Recent cryo-EM studies have revealed how these compounds, as well as other related molecules, are bound to integrase ( Fig. 4 J) [98] , [99] , coordinating two Mg 2+ ions in the active site. The structure of a resistant mutant in complex with bictegravir provides insights into the mechanism of resistance.…”

mentioning

confidence: 99%

Cryo-EM as a powerful tool for drug discovery

Drie¹,

Tong

2020

Bioorganic & Medicinal Chemistry Letters

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Structural basis of second-generation HIV integrase inhibitor action and viral resistance

Cited by 83 publications

References 64 publications

Influence of the amino-terminal sequence on the structure and function of HIV integrase

Influence of the amino-terminal sequence on the structure and function of HIV integrase

Systemic in Silico Screening in Drug Discovery for Coronavirus Disease (COVID-19) with an Online Interactive Web Server

Cryo-EM as a powerful tool for drug discovery

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