Repurposing BCL-2 and Jak 1/2 inhibitors: Cure and treatment of HIV-1 and other viral infections

Reece, Monica D.; Song, Colin; Hancock, Sarah C.; Ribeiro, Susan Pereira; Kulpa, Deanna A.; Gavegnano, Christina

doi:10.3389/fimmu.2022.1033672

Cited by 8 publications

(6 citation statements)

References 82 publications

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“…5A) . In inflammation disease, the activation of the NF-κB pathway, including the resultant upregulation of BCL-XL and c-Myb, can contribute to inflammation(Lawrence, 2009; Reece et al, 2022). This pathway plays a critical role in cell cycle regulation and is heavily involved in cancer pathogenesis due to its influence on cell proliferation and apoptosis.…”

Section: Resultsmentioning

confidence: 99%

Elucidating Molecular Mechanism and Chemical Space of Chalcones through Knowledge Graph and Machine Learning: A Combined Bio-Cheminformatic Pipeline

Manaithiya,

Bhowmik,

Acharjee

et al. 2024

Preprint

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We developed a bio-cheminformatics method, exploring disease inhibition mechanisms using machine learning-enhanced quantitative structure-activity relationship (ML-QSAR) models and knowledge-driven neural networks. ML-QSAR models were developed using molecular fingerprint descriptors and the Ran-dom Forest algorithm to explore the chemical spaces of Chalcones inhibitors against diverse disease prop-erties, including antifungal, anti-inflammatory, anticancer, antimicrobial, and antiviral effects. We gener-ated and validated robust machine learning-based bioactivity prediction models ((https://ashspred.streamlit.app/) for the top genes. These models underwent ROC and applicability do-main analysis, followed by molecular docking studies to elucidate the molecular mechanisms of the mole-cules. Through comprehensive neural network analysis, crucial genes such as AKT1, HSP90A1, SRC, and STAT3 were identified. The PubChem fingerprint-based model revealed key descriptors: PubchemFP521 for AKT1, PubchemFP180 for SRC, PubchemFP633 for HSP90, and PubchemFP145 and PubchemFP338 for STAT3, consistently contributing to bioactivity across targets. Notably, chalcone derivatives demon-strated significant bioactivity against target genes, with compound RA1 displaying a predictive pIC50 value of 5.76 against HSP90A and strong binding affinities across other targets. Compounds RA5 to RA7 also exhibited high binding affinity scores comparable to or exceeding existing drugs. These findings empha-size the importance of knowledge-based neural network-based research for developing effective drugs against diverse disease properties. These interactions warrant further in vitro and in vivo investigations to elucidate their potential in rational drug design. The presented models provide valuable insights for inhibi-tor design and hold promise for drug development. Future research will prioritize investigating these mol-ecules for mycobacterium tuberculosis, enhancing the comprehension of effectiveness in addressing infec-tious diseases.

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Section: Resultsmentioning

confidence: 99%

Elucidating Molecular Mechanism and Chemical Space of Chalcones through Knowledge Graph and Machine Learning: A Combined Bio-Cheminformatic Pipeline

Manaithiya,

Bhowmik,

Acharjee

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…In addition to reducing replication and cell-to-cell spread, inhibition of the inflammatory mediator cyclooxygenase-2 (COX-2) also decreased the lytic reactivation of Epstein-Barr virus (EBV). JAK/STAT inhibitors have also been shown to exhibit antiviral activity against numerous viruses including HIV (22)(23)(24), Zika (25), and SARS-CoV-2 (26).…”

Section: Discussionmentioning

confidence: 99%

“…JAK/STAT inhibitors have also been shown to inhibit a variety of viruses. HIV replication (22), viral reservoir establishment (23), and encephalitis (24) have all been reduced by JAK/STAT inhibitors. In addition to HIV, Zika, and SARS-CoV-2, virus replication was also inhibited in the presence of JAK/STAT inhibitors (25,26).…”

Section: Introductionmentioning

confidence: 99%

Anti-inflammatory compounds reduce equine herpesvirus type 1 replication and cell-to-cell spread

Black

Frampton

2023

Front. Vet. Sci.

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Equine herpesvirus type 1 (EHV-1) is a highly transmissible pathogen that leads to a variety of clinical disease outcomes in infected horses. A major sequela that can occur after an EHV-1 infection is a neurological disease termed equine herpesvirus myeloencephalopathy (EHM). Clinical manifestations of EHM include fever, ataxia, incontinence, and partial to full paralysis, which may ultimately lead to the euthanization of the infected horse. To develop an effective treatment strategy for EHM, it is critical that the specific virus–host interactions that lead to EHM be investigated so that safe and effective therapeutic interventions can be developed and delivered. In this study, we examined the ability of four non-steroidal anti-inflammatory drugs (NSAIDs), a steroidal anti-inflammatory drug (dexamethasone), a Rho-kinase (ROCK) inhibitor, and a JAK/STAT inhibitor (AG490) to reduce EHV-1 virus yields and cell-to-cell spread. We show that the NSAID, flunixin meglumine (FM), and the JAK/STAT inhibitor, AG490, significantly reduced virus yields in endothelial and epithelial cell lines, and this inhibition was similar for two neurologic and two non-neurologic EHV-1 strains. In addition to reducing virus yields, AG490 and FM also significantly reduced the ability of EHV-1 to spread laterally from cell to cell.

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“…Dimerized pSTAT5 undergoes nuclear translocation and binds to the promoter region of the BCL-2 gene to enhance its transcription. Jak 1/2 inhibitors such as ruxolitinib and baricitinib are FDA-approved medications that can block this pathway upstream of BCL-2 [40]. Clinical trials are currently underway to assess whether this strategy might have an impact on HIV reservoirs, with baricitinib currently being evaluated in the context of central nervous system inflammation and reservoir size in PWH (NCT05452564).…”

Section: Key Pointsmentioning

confidence: 99%

Pharmacological approaches to promote cell death of latent HIV reservoirs

Pinzone,

Shan

2023

Current Opinion in HIV and AIDS

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Purpose of review HIV requires lifelong antiviral treatment due to the persistence of a reservoir of latently infected cells. Multiple strategies have been pursued to promote the death of infected cells. Recent findings Several groups have focused on multipronged approaches to induce apoptosis of infected cells. One approach is to combine latency reversal agents with proapoptotic compounds and cytotoxic T cells to first reactivate and then clear infected cells. Other strategies include using natural killer cells or chimeric antigen receptor cells to decrease the size of the reservoir. A novel strategy is to promote cell death by pyroptosis. This mechanism relies on the activation of the caspase recruitment domain-containing protein 8 (CARD8) inflammasome by the HIV protease and can be potentiated by nonnucleoside reverse transcriptase inhibitors. Summary The achievement of a clinically significant reduction in the size of the reservoir will likely require a combination strategy since none of the approaches pursued so far has been successful on its own in clinical trials. This discrepancy between promising in vitro findings and modest in vivo results highlights the hurdles of identifying a universally effective strategy given the wide heterogeneity of the HIV reservoirs in terms of tissue location, capability to undergo latency reversal and susceptibility to cell death.

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Repurposing BCL-2 and Jak 1/2 inhibitors: Cure and treatment of HIV-1 and other viral infections

Cited by 8 publications

References 82 publications

Elucidating Molecular Mechanism and Chemical Space of Chalcones through Knowledge Graph and Machine Learning: A Combined Bio-Cheminformatic Pipeline

Elucidating Molecular Mechanism and Chemical Space of Chalcones through Knowledge Graph and Machine Learning: A Combined Bio-Cheminformatic Pipeline

Anti-inflammatory compounds reduce equine herpesvirus type 1 replication and cell-to-cell spread

Pharmacological approaches to promote cell death of latent HIV reservoirs

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