Rational correction of pathogenic conformational defects in HTRA1.

Loss-of-function mutations in the homotrimeric serine protease HTRA1 cause cerebral vasculopathy. Here, we establish independent approaches to achieve the functional correction of trimer assembly defects. Focusing on the prototypical R274Q mutation, we identify an HTRA1 variant that promotes trimer formation thus restoring enzymatic activity in vitro. Genetic experiments in Htra1R274Q mice further demonstrate that expression of this protein-based corrector in trans is sufficient to stabilize HtrA1-R274Q and restore the proteomic signature of the brain vasculature. An alternative approach employs supramolecular chemical ligands that shift the monomer-trimer equilibrium towards proteolytically active trimers. Moreover, we identify a peptidic ligand that activates HTRA1 monomers. Our findings open perspectives for tailored protein repair strategies.

Drug repurposing screen identifies novel anti-inflammatory activity of sunitinib in macrophages.

Inflammation is a driver of human disease and an unmet clinical need exists for new anti-inflammatory medicines. As a key cell type in both acute and chronic inflammatory pathologies, macrophages are an appealing therapeutic target for anti-inflammatory medicines. Drug repurposing - the use of existing medicines for novel indications - is an attractive strategy for the identification of new anti-inflammatory medicines with reduced development costs and lower failure rates than de novo drug discovery. In this study, FDA-approved medicines were screened in a murine macrophage NF-κB reporter cell line to identify potential anti-inflammatory drug repurposing candidates. The multi-tyrosine kinase inhibitor sunitinib was found to be a potent inhibitor of NF-κB activity and suppressor of inflammatory mediator production in murine bone marrow derived macrophages. Furthermore, oral treatment with sunitinib in mice was found to reduce TNFα production, inflammatory gene expression and organ damage in a model of endotoxemia via inhibition of NF-κB. Finally, we revealed sunitinib to have immunomodulatory effects in a model of chronic cardiovascular inflammation by reducing circulating TNFα. This study validates drug repurposing as a strategy for the identification of novel anti-inflammatory medicines and highlights sunitinib as a potential drug repurposing candidate for inflammatory disease via inhibition of NF-κB signalling.

Drug repurposing in cardiovascular inflammation: Successes, failures, and future opportunities.

Drug repurposing is an attractive, pragmatic approach to drug discovery that has yielded success across medical fields over the years. The use of existing medicines for novel indications enables dramatically reduced development costs and timescales compared with de novo drug discovery and is therefore a promising strategy in cardiovascular disease, where new drug approvals lag significantly behind that of other fields. Extensive evidence from pre-clinical and clinical studies show that chronic inflammation is a driver of pathology in cardiovascular disease, and many efforts have been made to target cardiovascular inflammation therapeutically. This approach has been met with significant challenges however, namely off-target effects associated with broad-spectrum immunosuppression, particularly in long-term conditions such as cardiovascular disease. Nevertheless, multiple anti-inflammatory medicines have been assessed for efficacy in cardiovascular clinical trials, with most of these being repurposed from their original indications in autoimmune conditions like rheumatoid arthritis. In this review, we discuss the mixed successes of clinical trials investigating anti-inflammatory drugs in cardiovascular disease, with examples such as anti-cytokine monoclonal antibodies, colchicine, and methotrexate. Looking to the future, we highlight potential new directions for drug repurposing in cardiovascular inflammation, including the emerging concepts of drug re-engineering and chrono-pharmacology.

NF-κB Signaling and Inflammation-Drug Repurposing to Treat Inflammatory Disorders?

NF-κB is a central mediator of inflammation, response to DNA damage and oxidative stress. As a result of its central role in so many important cellular processes, NF-κB dysregulation has been implicated in the pathology of important human diseases. NF-κB activation causes inappropriate inflammatory responses in diseases including rheumatoid arthritis (RA) and multiple sclerosis (MS). Thus, modulation of NF-κB signaling is being widely investigated as an approach to treat chronic inflammatory diseases, autoimmunity and cancer. The emergence of COVID-19 in late 2019, the subsequent pandemic and the huge clinical burden of patients with life-threatening SARS-CoV-2 pneumonia led to a massive scramble to repurpose existing medicines to treat lung inflammation in a wide range of healthcare systems. These efforts continue and have proven to be controversial. Drug repurposing strategies are a promising alternative to de novo drug development, as they minimize drug development timelines and reduce the risk of failure due to unexpected side effects. Different experimental approaches have been applied to identify existing medicines which inhibit NF-κB that could be repurposed as anti-inflammatory drugs.