CARD8 inflammasome sensitization through DPP9 inhibition enhances NNRTI-triggered killing of HIV-1-infected cells

Clark, Kolin M.; Wang, Qiankun; Shan, Liang

doi:10.1101/2021.09.01.458624

Cited by 5 publications

(2 citation statements)

References 36 publications

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“…Some obstacles toward implementation of this strategy include the high concentrations of NNRTIs required for CARD8 inflammasome activation in HIV-1-infected cells and the fact that NNRTIs bind human serum proteins, reducing their bioavailability in vivo [74]. A recent preprint suggests that CARD8 sensitization through inhibition of DPP9, a negative regulator of CARD8, can overcome these obstacles and enhance NNRTI-triggered killing of HIV-1-infected cells [75]. Furthermore, drug screening for compounds that more efficiently trigger Gag-Pol dimerization and premature PR activation is a promising strategy to identify novel antivirals that can efficiently induce CARD8 inflammasome-dependent killing of HIV-1-infected cells with few side effects.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Beyond Inhibition: A Novel Strategy of Targeting HIV-1 Protease to Eliminate Viral Reservoirs

Kim¹,

Liang²

2022

Preprint

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HIV-1 protease (PR) is a viral enzyme that cleaves viral polyprotein precursors to convert them into functional forms, a process essential to generate infectious viral particles. Due to its broad substrate specificity, HIV-1 PR can also cleave certain host cell proteins. Several studies have identified host cell substrates of HIV-1 PR and described the potential impact of their cleavage on HIV-1-infected cells. Of particular interest is the interaction between PR and the caspase recruitment domain-containing protein 8 (CARD8) inflammasome. While PR typically has low levels of intracellular activity prior to viral budding, induction of premature PR activation to trigger CARD8-mediated cell killing may help eliminate latent reservoirs in people living with HIV. In this review, we discuss the viral and host substrates of HIV-1 protease and highlight potential applications and advantages of targeting CARD8 sensing of HIV-1 PR.

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Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Beyond Inhibition: A Novel Strategy of Targeting HIV-1 Protease to Eliminate Viral Reservoirs

Kim¹,

Liang²

2022

Preprint

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“…Based on this concept, our group recently found that DPP9 inhibition reduces the threshold concentration of NNRTIs needed to trigger pyroptosis in HIV-infected cells. [ 65 ] Another major obstacle for targeting the inflammasome for the treatment of HIV-1 infection is cytokine release during inflammasome activation. However, it is generally accepted that CD4 + T cells do not secrete the inflammatory cytokines IL-1β or IL-18.…”

Section: Targeting the Inflammasome For The Treatment Of Hiv-1 Infectionmentioning

confidence: 99%

Inflammasomes in Human Immunodeficiency Virus Type 1 Infection

Wang¹,

Shan²

2022

Infect Dis Immun

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Innate immune responses are the host's first line of defense against human immunodeficiency virus type 1 (HIV-1) infection, with pattern recognition receptors detecting viral specific pathogen-associated molecular patterns and initiating antiviral responses. In response to HIV-1 nucleic acids or proteins, some pattern recognition receptors have the ability to assemble a large multiprotein complex called the inflammasome, which triggers pro-inflammatory cytokine release and a form of lytic programmed cell death called pyroptosis. Here, we review our current understanding of the mechanism of the inflammasome in sensing HIV-1 infection. Furthermore, we discuss the contribution of inflammasome activation in HIV-1 pathogenesis as well as potential strategies of targeting inflammasome activation for the treatment of HIV-1 infection.

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Molecular Targeted Engagement of DPP9 in Rat Tissue Using CETSA, SP3 Processing, and Absolute Quantitation Mass Spectrometry

Mazur,

Shyong,

Huang

et al. 2024

ACS Chem. Biol.

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The cellular thermal shift assay (CETSA) provides a means of understanding the extent to which a small molecule ligand associates with a protein target of therapeutic interest, thereby inferring target engagement. Better analytical detection methods, including mass spectrometry, are being implemented to improve quantitation within these assays, providing both absolute quantitation and a very high analyte specificity. To understand the target engagement, and hence inhibition, of the protein dipeptidyl peptidase 9 (DPP9) in rat tissue, CETSA experiments, coupled with single-pot, solid-phase-enhanced sample preparation ("SP3") and absolute quantitation by high-resolution mass spectrometry, demonstrated a temperature-dependent "melting curve" by ex vivo incubation of compound with rat tissue and further demonstrated in vivo engagement by a dose-dependent response to treatment. These experiments illustrate the ability to extend the CETSA to in vivo dosed-animal samples using absolute quantitation of DPP9 by mass spectrometry and demonstrate a viable path for interrogating therapeutic molecules for drug discovery.

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CARD8 inflammasome sensitization through DPP9 inhibition enhances NNRTI-triggered killing of HIV-1-infected cells

Cited by 5 publications

References 36 publications

Beyond Inhibition: A Novel Strategy of Targeting HIV-1 Protease to Eliminate Viral Reservoirs

Beyond Inhibition: A Novel Strategy of Targeting HIV-1 Protease to Eliminate Viral Reservoirs

Inflammasomes in Human Immunodeficiency Virus Type 1 Infection

Molecular Targeted Engagement of DPP9 in Rat Tissue Using CETSA, SP3 Processing, and Absolute Quantitation Mass Spectrometry

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