Optimization of unique, uncharged thioesters as inhibitors of HIV replication

Srivastava, Pratibha; Schito, Marco; Fattah, Rasem J.; Hara, Toshiaki; Hartman, Tracy L.; Buckheit, Robert W.; Turpin, Jim A.; Inman, John K.; Appella, Ettore

doi:10.1016/j.bmc.2004.09.032

Cited by 48 publications

(56 citation statements)

References 47 publications

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“…, have been reported previously (35). Compound synthesis for these experiments was carried out as described previously (35).…”

Section: N-[2-(345-trimethoxybenzoylthio)benzoyl]-l-alaninamide (Samentioning

confidence: 99%

“…It is important for reverse transcription and integration in the early stage of the life cycle, and NCp7 is required for dimerization and packaging of the viral genome late in the life cycle (1,2,5,9,18,26,28). Additionally, the protein is highly conserved among all retroviruses except spumavirus (35). The high genetic barrier to mutation combined with its role in multiple stages of the infectious cycle makes NCp7 an ideal candidate for targeting the transmission of HIV.…”

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confidence: 99%

“…A number of compounds have been developed to date that interact with the retroviral zinc-binding domains with various degrees of efficacy and toxicity (29,30,35,38,39). In this study, we have examined three analogs of the latest class of inhibitor-the S-acyl-2-mercaptobenzamide thioesters (SAMTs) (Fig.…”

mentioning

confidence: 99%

“…These compounds function through ejection of the zinc ion, an irreversible process due to covalent modification of the zinc-coordinating cysteine residues and lysine residues required for proper tetrahedral geometry (21). The SAMTs inhibit a range of wild-type retroviruses, as well as a multidrugresistant isolate of HIV-1 (35). Furthermore, the compounds show virucidal activity, the ability to inhibit virus expression from latently infected cells, and inhibition of cell-to-cell transmission (35).…”

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confidence: 99%

“…The SAMTs inhibit a range of wild-type retroviruses, as well as a multidrugresistant isolate of HIV-1 (35). Furthermore, the compounds show virucidal activity, the ability to inhibit virus expression from latently infected cells, and inhibition of cell-to-cell transmission (35). Here, we have evaluated these compounds for their efficacy in inhibiting HIV-1 transmission in cell-based antiviral assays, ex vivo cervical tissue explant culture, and the rhesus macaque challenge model, with a view to further develop these candidates as topical microbicides for the prevention of the sexual transmission of HIV.…”

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confidence: 99%

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Human Immunodeficiency Virus Type 1 Nucleocapsid Inhibitors Impede trans Infection in Cellular and Explant Models and Protect Nonhuman Primates from Infection

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Here, we report that the S-acyl-2-mercaptobenzamide thioester (SAMT) class of human immunodeficiency virus type 1 (HIV-1) nucleocapsid protein (NCp7) inhibitors was able to prevent transmission of HIV-1 from infected cells, including primary cells. Furthermore, when SAMTs were introduced during an HIV-1 challenge of cervical explant tissue, inhibition of dissemination of infectious virus by cells emigrating from the tissue explants was observed. Preliminary studies using a rhesus macaque vaginal challenge model with mixed R5 and X4 simian-human immunodeficiency virus infection found that five of six monkeys were completely protected, with the remaining animal being partially protected, infected only by the R5 virus. These data suggest that SAMTs may be promising new drug candidates for further development in anti-HIV-1 topical microbicide applications.

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“…, have been reported previously (35). Compound synthesis for these experiments was carried out as described previously (35).…”

Section: N-[2-(345-trimethoxybenzoylthio)benzoyl]-l-alaninamide (Samentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Human Immunodeficiency Virus Type 1 Nucleocapsid Inhibitors Impede trans Infection in Cellular and Explant Models and Protect Nonhuman Primates from Infection

Wallace

Cheng‐Mayer

Schito

et al. 2009

J Virol

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Targeting HIV‐1 Integrase Zinc Binding Motif

Sechi

Carcelli

Rogolino

et al. 2009

Drug Design of Zinc‐Enzyme Inhibitors

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Targeting a Dark Excited State of HIV‐1 Nucleocapsid by Antiretroviral Thioesters Revealed by NMR Spectroscopy

et al. 2018

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HIV-1 nucleocapsid (NCp7) is at wo Cys 2 HisCys zinc knuckle (N-Zn and C-Zn) protein that playsakey role in viral replication. NCp7 conformational dynamics is characterizedb yNMR relaxation dispersion and chemical exchange saturation transfer measurements.W hile the N-Zn knuckle is conformationally stable,the C-Zn knuckle interconverts on the millisecond timescale between the major state,inwhich the zinc is coordinated by three cysteines and ahistidine,and two folded minor species (with populations around 1%)i nw hich one of the coordination bonds (Cys413-Sg-Zn or His421-Ne2-Zn) is hydrolyzed.T hese findings explain why antiretroviral thioesters specifically disrupt the C-Zn knuckle by initial acylation of Cys413, and showt hat transient, sparsely-populated ("dark"), excited states of proteins can present effective targets for rational drug design. Dr.L .Deshmukh Present address:D epartment of Chemistry and Biochemistry, Universityo fC alifornia, San Diego La Jolla, CA 92093 (USA) Supportinginformation and the ORCID identification number(s) for the author(s) of this article can be found under: https://doi.

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Optimization of unique, uncharged thioesters as inhibitors of HIV replication

Cited by 48 publications

References 47 publications

Human Immunodeficiency Virus Type 1 Nucleocapsid Inhibitors Impede trans Infection in Cellular and Explant Models and Protect Nonhuman Primates from Infection

Human Immunodeficiency Virus Type 1 Nucleocapsid Inhibitors Impede trans Infection in Cellular and Explant Models and Protect Nonhuman Primates from Infection

Targeting HIV‐1 Integrase Zinc Binding Motif

Targeting a Dark Excited State of HIV‐1 Nucleocapsid by Antiretroviral Thioesters Revealed by NMR Spectroscopy

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