Ebselen, a Small-Molecule Capsid Inhibitor of HIV-1 Replication

Thenin-Houssier, Suzie; Vera, Ian Mitchelle S. de; Pedró-Rosa, Laura; Brady, Angela; Richard, Audrey S.; Konnick, Briana; Opp, Silvana; Buffone, Cindy; Fuhrmann, Jakob; Kota, Smitha; Billack, Blasé; Pįętka-Ottlik, Magdalena; Tellinghuisen, Timothy L.; Choe, Hyeryun; Spicer, Timothy; Scampavia, Louis; Díaz-Griffero, Felipe; Kojetin, D.J.; Valente, Susana T.

doi:10.1128/aac.02574-15

Cited by 102 publications

(74 citation statements)

References 51 publications

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“…[8][9][10][11][12][13][14][15]20,21 Ebselen (2-phenylbenzisoselenazol-3(2H)-one) and its analogues have received particular attention as glutathione peroxidase mimics, 8,11,15 antioxidant and anti-inflammatory agents. [13][14][15] Furthermore, the continuing interest in this class of compounds has led to the development of various structures with antiviral [22][23][24][25][26] and antimicrobial [24][25][26][27] properties. In this work we report a convenient synthetic route to a series of new alkylated and methoxylated benzisoselanazol-3(2H)-ones 4 and bis(2-carbamoylaryl)diselenides 6 which were tested for antiviral and antimicrobial activity in biological studies.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of new alkylated and methoxylated analogues of ebselen with antiviral and antimicrobial properties

Pįętka-Ottlik¹,

Burda-Grabowska²,

Woźna³

et al. 2017

Arkivoc

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A series of new mono and disubstituted alkylated and methoxylated benzisoselanzol-3(2H)-ones and bis(2-carbamoylaryl)diselenides were prepared in yields ranging from 55% to 95% starting from anthranilic acid and were evaluated for antiviral and antimicrobial activity. The compounds exhibited antiviral activity against Human herpes virus 1 and Encephalomyocarditis virus as well as antimicrobial activity against Staphylococcus aureus, Bacillus subtilis, Escherichia coli and Candida albicans.

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Section: Introductionmentioning

confidence: 99%

Synthesis of new alkylated and methoxylated analogues of ebselen with antiviral and antimicrobial properties

Pįętka-Ottlik¹,

Burda-Grabowska²,

Woźna³

et al. 2017

Arkivoc

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“…Given the broad network of essential interactions between CA molecules within the lattice and cellular factors in target cells, HIV-1 CA is emerging as a viable new target for anti-retroviral therapy [17]. Compounds that target CA can disrupt the assembly of the CA lattice and particle morphogenesis [91, 126–129], alter the stability of the CA lattice and/or uncoating [91, 130–132], and inhibit reverse transcription [91, 126, 129, 130, 132, 133] and nuclear entry [134–136] in target cells. Expectedly, CA is highly sensitive to mutations [137], making it an exceptionally viable drug target as resistance mutations would likely come at a high fitness cost to the virus.…”

Section: Discussionmentioning

confidence: 99%

Capsid lattice destabilization leads to premature loss of the viral genome and integrase enzyme during HIV-1 infection

Eschbach

Elliott

et al. 2020

Preprint

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The human immunodeficiency virus type 1 (HIV-1) capsid (CA) protein forms a conical lattice around the viral ribonucleoprotein complex (vRNP) consisting of a dimeric viral genome and associated proteins, together constituting the viral core. Upon entry into target cells, the viral core undergoes a process termed uncoating, during which CA molecules are shed from the lattice. Although the timing and degree of uncoating are important for reverse transcription and integration, the molecular basis of this phenomenon remains unclear. Using complementary approaches, we assessed the impact of core destabilization on the intrinsic stability of the CA lattice in vitro and fates of viral core components in infected cells. We found that substitutions in CA can impact the intrinsic stability of the CA lattice in vitro in the absence of vRNPs, which mirrored findings from assessment of CA stability in virions. Altering CA stability tended to increase the propensity to form morphologically aberrant particles, in which the vRNPs were mislocalized between the CA lattice and the viral lipid envelope. Importantly, destabilization of the CA lattice led to premature dissociation of CA from vRNPs in target cells, which was accompanied by proteasomal-independent losses of the viral genome and integrase enzyme. Overall, our studies show that the CA lattice protects the vRNP from untimely degradation in target cells and provide the mechanistic basis of how CA stability influences reverse transcription.AUTHOR SUMMARYThe human immunodeficiency virus type 1 (HIV-1) capsid (CA) protein forms a conical lattice around the viral RNA genome and the associated viral enzymes and proteins, together constituting the viral core. Upon infection of a new cell, viral cores are released into the cytoplasm where they undergo a process termed “uncoating”, i.e. shedding of CA molecules from the conical lattice. Although proper and timely uncoating has been shown to be important for reverse transcription, the molecular mechanisms that link these two events remain poorly understood. In this study, we show that destabilization of the CA lattice leads to premature dissociation of CA from viral cores, which exposes the viral genome and the integrase enzyme for degradation in target cells. Thus, our studies demonstrate that the CA lattice protects the viral ribonucleoprotein complexes from untimely degradation in target cells and provide the first causal link between how CA stability affects reverse transcription.

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“…There are few reports of non-peptidic compounds targeting CTD of CA. [7][8][9][10][11] The other reported compounds bind to the NTD of CA and some of them affect capsid assembly. Three independent binding sites have been defined in the NTD.…”

Section: Introductionmentioning

confidence: 98%

Synthesis and evaluation of 2-pyridinylpyrimidines as inhibitors of HIV-1 structural protein assembly

Kožíšek

Štěpánek

Parkan

et al. 2016

Bioorganic & Medicinal Chemistry Letters

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In an effort to identify an HIV-1 capsid assembly inhibitor with improved solubility and potency, we synthesized two series of pyrimidine analogues based on our earlier lead compound N-(4-(ethoxycarbonyl)phenyl)-2-(pyridine-4-yl)quinazoline-4-amine. In vitro binding experiments showed that our series of 2-pyridine-4-ylpyrimidines had IC50 values higher than 28μM. Our series of 2-pyridine-3-ylpyrimidines exhibited IC50 values ranging from 3 to 60μM. The congeners with a fluoro substituent introduced at the 4-N-phenyl moiety, along with a methyl at C-6, represent potent HIV capsid assembly inhibitors binding to the C-terminal domain of the capsid protein.

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Ebselen, a Small-Molecule Capsid Inhibitor of HIV-1 Replication

Cited by 102 publications

References 51 publications

Synthesis of new alkylated and methoxylated analogues of ebselen with antiviral and antimicrobial properties

Synthesis of new alkylated and methoxylated analogues of ebselen with antiviral and antimicrobial properties

Capsid lattice destabilization leads to premature loss of the viral genome and integrase enzyme during HIV-1 infection

Synthesis and evaluation of 2-pyridinylpyrimidines as inhibitors of HIV-1 structural protein assembly

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