作者: You, Hongbo ; Liang, Shuang ; Wang, Zhenggang ; Guo, Fengjing ; Zhang, Jiaming ; He, Zhiyi ; Chen, Anmin ; Lu, Rui ; Xu, Shimeng ; Qu, Yunkun ; Cheng, Peng ; Lv, Zhengtao

ObjectivesTANK-binding kinase 1 (TBK1) is pivotal in autoimmune and inflammatory diseases, yet its role in osteoarthritis (OA) remains elusive. This study sought to elucidate the effect of the TBK1 inhibitor BX795 on OA and to delineate the underlying mechanism by which it mitigates OA.MethodsInterleukin-1 Beta (IL-1β) was utilized to simulate inflammatory responses and extracellular matrix degradation in vitro. In vivo, OA was induced in 8-week-old mice through destabilization of the medial meniscus surgery. The impact of BX795 on OA was evaluated using histological analysis, X-ray, micro-CT, and the von Frey test. Additionally, Western blot, RT-qPCR, and immunofluorescence assays were conducted to investigate the underlying mechanisms of BX795.ResultsPhosphorylated TBK1 (P-TBK1) levels were found to be elevated in OA knee cartilage of both human and mice. Furthermore, intra-articular injection of BX795 ameliorated cartilage degeneration and alleviated OA-associated pain. BX795 also counteracted the suppression of anabolic processes and the augmentation of catabolic activity, inflammation, and senescence observed in the OA mice. In vitro studies revealed that BX795 reduced P-TBK1 levels and reversed the effects of anabolism inhibition, catabolism promotion, and senescence induction triggered by IL-1β. Mechanistically, BX795 inhibited the IL-1β-induced activation of the cGAS-STING and TLR3-TRIF signaling pathways in chondrocytes.ConclusionsPharmacological inhibition of TBK1 with BX795 protects articular cartilage by inhibiting the activation of the cGAS-STING and TLR3-TRIF signaling pathways. This action attenuates inflammatory responses and cellular senescence, positioning BX795 as a promising therapeutic candidate for OA treatment.The translational potential of this articleThis study furnishes experimental evidence and offers a potential mechanistic explanation supporting the efficacy of BX795 as a promising candidate for OA treatment.

2024-01-12·ACS Infectious Diseases

Oral Self-Nanoemulsifying System Containing Ionic Liquid of BX795 Is Effective against Genital HSV-2 Infection in Mice

Article

作者: Singh, Sudhanshu Kumar ; Mali, Jaishree ; Sutar, Yogesh ; Adams, Joseph ; Yadavalli, Tejabhiram ; Date, Abhijit A ; Dhoble, Sagar ; Shukla, Deepak

BX795 is an emerging drug candidate that has shown a lot of promise as a next-generation non-nucleoside antiviral agent for the topical treatment of herpes simplex virus type-1 (HSV-1) and herpes simplex virus type-2 (HSV-2) infections. Our studies indicated that BX795 has limited oral bioavailability, which could be attributed to its low and pH-dependent solubility. Lipid-based formulations such as self-nanoemulsifying systems (SNESs) can improve the solubility and oral bioavailability of BX795, but the poor lipid solubility of BX795 further limits the development of SNES. To improve the loading of BX795 into SNES, we evaluated the ability of various bulky and biocompatible anions to transform BX795 into an ionic liquid (IL) with higher lipid solubility. Our studies showed that sodium lauryl sulfate and docusate sodium were able to transform BX795 into IL. Compared to pure BX795, the developed BX795 ILs showed differential in vitro cytocompatibility to HeLa cells but exhibited similar in vitro antiviral activity against HSV-2. Interestingly, BX795 docusate (BX795-Doc), an IL of BX795 with ∼135-fold higher lipid solubility than pure BX795, could be successfully incorporated into an SNES, and the developed BX795-Doc-SNES could readily form nanoemulsions of size ≤200 nm irrespective of the pH of the buffer used for dilution. Our in vitro studies showed that BX795-Doc-SNES retained the inherent antiviral activity against HSV-2 and showed similar in vitro cytocompatibility, indicating the availability of BX795 from the SNES in vitro. Finally, orally delivered SNES containing BX795-Doc showed a significant reduction in HSV-2 infection in mice compared to the untreated control. Thus, the transformation of BX795 into IL and the subsequent incorporation of the BX795 IL into the SNES are an effective strategy to improve oral therapy of genital herpes infection.

2023-09-01·Biomedicine & Pharmacotherapy

Tolerability, pharmacokinetics, and anti-herpetic activity of orally administered BX795

Article

作者: Singh, Sudhanshu Kumar ; Date, Abhijit A ; Yadavalli, Tejabhiram ; Shukla, Deepak

Herpes simplex viruses type-1 (HSV-1) and type-2 (HSV-2) are ubiquitous human pathogens causing serious pathologies in the ocular, orofacial and anogenital regions. While current treatments such as nucleoside analogs are effective in most cases, the emergence of drug resistance necessitates the development of newer antivirals with different mechanisms of action. In this regard, BX795, a small molecule inhibitor has shown significant benefit in the treatment of herpesvirus infections previously when dosed topically. However, the efficacy of BX795's systemic dosage remains to be tested. In this study, we evaluated acute and short-term toxicity of orally administered BX795 at a concentration of 400 and 100 mg/kg respectively in mice. This was followed by an evaluation of pharmacokinetics and tissue distribution of BX795 on intravenous and oral administration. Based on these studies, we performed an in vivo antiviral study using murine models of ocular HSV-1 and genital HSV-2 infection. Our results indicate that orally administered BX795 is very well tolerated, had oral bioavailability of 56%, and reached ocular and genital tissues within the first 15 min of dosing. Our studies indicate that BX795 administered orally can significantly reduce herpesvirus replication in the ocular and genital tissue.

100 项与 BX795 相关的药物交易

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