Repositioned Drugs for Inflammatory Diseases such as Sepsis, Asthma, and Atopic Dermatitis

Prakash, Annamneedi Venkata; Park, Jun Woo; Seong, Ju-Won; Kang, Tae Jin

doi:10.4062/biomolther.2020.001

Cited by 7 publications

(6 citation statements)

References 95 publications

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“…An example is TAK 242 (resatorvid), a small-molecule inhibitor of TLR4 signaling, initially developed as an anti-sepsis agent specifically disrupting the TLR4-TIRAP interaction with high selectivity and capable of inhibiting inflammatory mediator production at nanomolar levels [42][43][44] . Moreover, in order to speed up the drug development process and reduce the costs and time for clinical studies, drug repurposing has been employed 45 , resulting in drug candidates such as simvastatin 46 and several oncology drugs 47 .…”

Section: Discussionmentioning

confidence: 99%

Targeting Toll-like receptor-driven systemic inflammation by engineering an innate structural fold into drugs

Petruk,

Puthia,

Samsudin

et al. 2023

Nat Commun

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There is a clinical need for conceptually new treatments that target the excessive activation of inflammatory pathways during systemic infection. Thrombin-derived C-terminal peptides (TCPs) are endogenous anti-infective immunomodulators interfering with CD14-mediated TLR-dependent immune responses. Here we describe the development of a peptide-based compound for systemic use, sHVF18, expressing the evolutionarily conserved innate structural fold of natural TCPs. Using a combination of structure- and in silico-based design, nuclear magnetic resonance spectroscopy, biophysics, mass spectrometry, cellular, and in vivo studies, we here elucidate the structure, CD14 interactions, protease stability, transcriptome profiling, and therapeutic efficacy of sHVF18. The designed peptide displays a conformationally stabilized, protease resistant active innate fold and targets the LPS-binding groove of CD14. In vivo, it shows therapeutic efficacy in experimental models of endotoxin shock in mice and pigs and increases survival in mouse models of systemic polymicrobial infection. The results provide a drug class based on Nature´s own anti-infective principles.

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Section: Discussionmentioning

confidence: 99%

Targeting Toll-like receptor-driven systemic inflammation by engineering an innate structural fold into drugs

Petruk,

Puthia,

Samsudin

et al. 2023

Nat Commun

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“…Chemokines contribute to the pathogenesis of several diseases including rheumatoid arthritis, asthma, and sepsis [ 31 , 32 ]. MCP-1, a part of C –C chemokine family, controls the recruitment of neutrophils and Tregs [ 33 ].…”

Section: Discussionmentioning

confidence: 99%

Forsythiaside A prevents zymosan A-induced cell migration in neutrophil-differentiated HL-60 cells via PD-1/PD-L1 pathway

Zhang¹,

Li²,

Xu³

et al. 2023

Heliyon

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“…Moreover, 90 % of drug candidates fail in clinical trials due to safety and efficacy concerns. Because of extensive safety testing in pre-clinical animal models and in clinical trials [52,53], drug repurposing minimizes this risk of failure. Furthermore, drug repurposing offers the opportunity to rescue compounds that have undergone clinical testing and have good pharmacokinetic and safety profiles but have previously failed to achieve clinical approval due to lack of efficacy in their original indications.…”

Section: Drug Repurposing To Identify Nf-κb Inhibitorsmentioning

confidence: 99%

“…Alternatively, screens can be performed to identify diseases with shared molecular targets and thus shared treatment options. Many successful drug repurposing efforts combine drug-and disease-based approaches [55,56].…”

Section: Computer Based Drug Repurposing Strategiesmentioning

confidence: 99%

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

Roberti¹,

Chaffey²,

Greaves³

2022

Preprint

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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 these efforts continue to be con-troversial. 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.

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Repositioned Drugs for Inflammatory Diseases such as Sepsis, Asthma, and Atopic Dermatitis

Cited by 7 publications

References 95 publications

Targeting Toll-like receptor-driven systemic inflammation by engineering an innate structural fold into drugs

Targeting Toll-like receptor-driven systemic inflammation by engineering an innate structural fold into drugs

Forsythiaside A prevents zymosan A-induced cell migration in neutrophil-differentiated HL-60 cells via PD-1/PD-L1 pathway

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

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