AtomNet-Aided OTUD7B Inhibitor Discovery and Validation

Chen, Jianfeng; Bolhuis, Derek L.; Laggner, Christian; Kong, Deyu; Yu, Le; Wang, Xiaodong; Emanuele, Michael J.; Brown, Nicholas G.; Liu, Pengda

doi:10.3390/cancers15020517

Cited by 8 publications

(5 citation statements)

References 38 publications

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“…To investigate this further, we identified small molecule binders of StARD1 through Virtual High-Throughput Screening (VHTS) using Atomwise's proprietary AI-based AtomNetÒ screening platform, as previously described [27,28]. Briefly, the sterol-binding domain of human apo-STARD1 (PDB: 3P0L [29]) was defined as shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

Mitochondrial dysfunction in NPC1‐deficiency is not rescued by drugs targeting the glucosylceramidase GBA2 and the cholesterol‐binding proteins TSPO and StARD1

Wheeler,

Bhardwaj,

Kenyon

et al. 2024

FEBS Letters

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Niemann–Pick type C disease (NPCD) is a rare neurodegenerative disorder most commonly caused by mutations in the lysosomal protein Niemann–Pick C1 (NPC1), which is implicated in cholesterol export. Mitochondrial insufficiency forms a significant feature of the pathology of this disease, yet studies attempting to address this are rare. The working hypothesis is that mitochondria become overloaded with cholesterol which renders them dysfunctional. We examined two potential protein targets—translocator protein (TSPO) and steroidogenic acute regulatory protein D1 (StARD1)—which are implicated in cholesterol transport to mitochondria, in addition to glucocerbrosidase 2 (GBA2), the target of miglustat, which is currently the only approved treatment for NPCD. However, inhibiting these proteins did not correct the mitochondrial defect in NPC1‐deficient cells.

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Section: Resultsmentioning

confidence: 99%

Mitochondrial dysfunction in NPC1‐deficiency is not rescued by drugs targeting the glucosylceramidase GBA2 and the cholesterol‐binding proteins TSPO and StARD1

Wheeler,

Bhardwaj,

Kenyon

et al. 2024

FEBS Letters

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“…The major neurological complication of CM is disruption of the BBB and patients surviving CM suffer from long term cognitive deficits. Therefore, clinical validation of drugs targeting OTUD7b such as the recently identified OTUD7B inhibitor 7Bi [ 64 ], may aid in preventing BBB dysfunction by dampening DC-dependent T cell responses and could be used as an adjunct therapy in combination with anti-malarial drugs directly targeting the parasite.…”

Section: Discussionmentioning

confidence: 99%

The deubiquitinating enzyme OTUD7b protects dendritic cells from TNF-induced apoptosis by stabilizing the E3 ligase TRAF2

et al. 2023

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The cytokine tumor necrosis factor (TNF) critically regulates the intertwined cell death and pro-inflammatory signaling pathways of dendritic cells (DCs) via ubiquitin modification of central effector molecules, but the intrinsic molecular switches deciding on either pathway are incompletely defined. Here, we uncover that the ovarian tumor deubiquitinating enzyme 7b (OTUD7b) prevents TNF-induced apoptosis of DCs in infection, resulting in efficient priming of pathogen-specific CD8+ T cells. Mechanistically, OTUD7b stabilizes the E3 ligase TNF-receptor-associated factor 2 (TRAF2) in human and murine DCs by counteracting its K48-ubiquitination and proteasomal degradation. TRAF2 in turn facilitates K63-linked polyubiquitination of RIPK1, which mediates activation of NF-κB and MAP kinases, IL-12 production, and expression of anti-apoptotic cFLIP and Bcl-xL. We show that mice with DC-specific OTUD7b-deficiency displayed DC apoptosis and a failure to induce CD8+ T cell-mediated brain pathology, experimental cerebral malaria, in a murine malaria infection model. Together, our data identify the deubiquitinating enzyme OTUD7b as a central molecular switch deciding on survival of human and murine DCs and provides a rationale to manipulate DC responses by targeting their ubiquitin network downstream of the TNF receptor pathway.

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“…To identify small molecule binders of RVFV Gc, a vHTS was performed using the AtomNet ® platform (Atomwise, Inc., San Francisco, CA, USA), as described previously [ 29 , 30 , 31 , 32 , 33 , 34 , 35 ]. A library of 8,062,379 small molecule with drug-like properties (Mcule v20191203) was screened and ranked using the post-fusion RVFV Gc protein (PDB ID: 6EGT, W821H mutant) [ 27 ].…”

Section: Methodsmentioning

confidence: 99%

Computer-Selected Antiviral Compounds: Assessing In Vitro Efficacies against Rift Valley Fever Virus

Alkan,

O’Brien,

Kenyon

et al. 2024

Viruses

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Rift Valley fever is a zoonotic viral disease transmitted by mosquitoes, impacting both humans and livestock. Currently, there are no approved vaccines or antiviral treatments for humans. This study aimed to evaluate the in vitro efficacy of chemical compounds targeting the Gc fusion mechanism. These compounds were identified through virtual screening of millions of commercially available small molecules using a structure-based artificial intelligence bioactivity predictor. In our experiments, a pretreatment with small molecule compounds revealed that 3 out of 94 selected compounds effectively inhibited the replication of the Rift Valley fever virus MP-12 strain in Vero cells. As anticipated, these compounds did not impede viral RNA replication when administered three hours after infection. However, significant inhibition of viral RNA replication occurred upon viral entry when cells were pretreated with these small molecules. Furthermore, these compounds exhibited significant inhibition against Arumowot virus, another phlebovirus, while showing no antiviral effects on tick-borne bandaviruses. Our study validates AI-based virtual high throughput screening as a rational approach for identifying effective antiviral candidates for Rift Valley fever virus and other bunyaviruses.

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AtomNet-Aided OTUD7B Inhibitor Discovery and Validation

Cited by 8 publications

References 38 publications

Mitochondrial dysfunction in NPC1‐deficiency is not rescued by drugs targeting the glucosylceramidase GBA2 and the cholesterol‐binding proteins TSPO and StARD1

Mitochondrial dysfunction in NPC1‐deficiency is not rescued by drugs targeting the glucosylceramidase GBA2 and the cholesterol‐binding proteins TSPO and StARD1

The deubiquitinating enzyme OTUD7b protects dendritic cells from TNF-induced apoptosis by stabilizing the E3 ligase TRAF2

Computer-Selected Antiviral Compounds: Assessing In Vitro Efficacies against Rift Valley Fever Virus

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