Drug Candidates for the Treatment of Immune Disease 2023

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: 26 July 2024 | Viewed by 4822

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Faculté de Pharmacie, Université Libre de Bruxelles, Campus Plaine CP 205/5, 1050 Brussels, Belgium
Interests: medicinal chemistry; organic synthesis; asymmetric synthesis
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Dear Colleagues,

Diseases involving immune disorders are a major problem in medicine, not only because of autoimmune diseases such as rheumatoid arthritis, lupus, and Crohn’s disease, but also because of the need to prevent transplant rejection and the effects of anticancer therapy. The medical armamentarium comprises a large number of substances that perform relatively well in helping patients to control these problems: corticosteroids, anticancer drugs with immunosuppressive properties (methotrexate, azathioprine, etc.), ciclosporin, rapalogues, monoclonal antibodies and several enzyme inhibitors. However, there are still numerous problems regarding the use of these drugs, and among them, side effects (especially opportunistic infections and cancers) and narrow therapeutic indices are the most severe. The research in this field should continue to find new compounds that will be safer for fighting these chronic pathological situations.

A significant number of drugs acting on the immune system have been approved, and most of them are enzyme inhibitors. These enzymes are involved in the synthesis of nucleic acid bases (e.g., inosine-5′-monophosphate dehydrogenase for mycophenolic acid and dihydroorotate dehydrogenase for leflunomide) or in signaling pathways (e.g., mTOR and JAK). However, to avoid side effects, it is clear that future immunomodulators should have more specific actions on the precise mechanisms involved in the immune disorders in order to limit life-threatening side effects.

Several enzymes have recently been described as potential new targets in autoimmune disorders. They represent new hopes for drugs having both high efficacy and safety. The biggest challenge remains obtaining selective and potent inhibitors of these enzymes. Since 2000, a series of attractive targets have been identified, such as indoleamine 2,3-dioxygenase 1, cyclic GMP-AMP synthase, pyruvate kinase M2 and arginase 1.

We are pleased to welcome papers reviewing the most recent research on this topic in the present thematic Special Issue.

We look forward to your contributions.

Dr. Francois Dufrasne
Guest Editor

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Keywords

  • immune system
  • immune disease
  • drugs

Published Papers (4 papers)

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Editorial

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2 pages, 153 KiB  
Editorial
Immune Diseases: Challenges, Hopes and Recent Achievements
by François Dufrasne
Pharmaceuticals 2024, 17(1), 97; https://doi.org/10.3390/ph17010097 - 11 Jan 2024
Viewed by 585
Abstract
Although they have been greatly described for about 50 years, we have gained a much greater understanding of immune diseases since the beginning of this millennium [...] Full article
(This article belongs to the Special Issue Drug Candidates for the Treatment of Immune Disease 2023)

Research

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22 pages, 18908 KiB  
Article
Methyl Canthin-6-one-2-carboxylate Restrains the Migration/Invasion Properties of Fibroblast-like Synoviocytes by Suppressing the Hippo/YAP Signaling Pathway
by Zongying Zhang, Yunhan Wang, Qiuyun Xu, Xiaorong Zhou, Yong Ling, Jie Zhang and Liming Mao
Pharmaceuticals 2023, 16(10), 1440; https://doi.org/10.3390/ph16101440 - 11 Oct 2023
Cited by 1 | Viewed by 851
Abstract
Rheumatoid arthritis (RA) is an inflammatory condition that causes severe cartilage degradation and synovial damage in the joints with multiple systemic implications. Previous studies have revealed that fibroblast-like synoviocytes (FLSs) play a pivotal role in the pathogenesis of RA. The appropriate regulation of [...] Read more.
Rheumatoid arthritis (RA) is an inflammatory condition that causes severe cartilage degradation and synovial damage in the joints with multiple systemic implications. Previous studies have revealed that fibroblast-like synoviocytes (FLSs) play a pivotal role in the pathogenesis of RA. The appropriate regulation of FLS function is an efficient approach for the treatment of this disease. In the present study, we explored the effects of methyl canthin-6-one-2-carboxylate (Cant), a novel canthin-6-one alkaloid, on the function of FLSs. Our data showed that exposure to Cant significantly suppressed RA-FLS migration and invasion properties in a dose-dependent manner. Meanwhile, pre-treatment with Cant also had an inhibitory effect on the release of several pro-inflammatory cytokines, including IL-6 and IL-1β, as well as the production of MMP1 and MMP3, which are important mediators of FLS invasion. In further mechanistic studies, we found that Cant had an inhibitory effect on the Hippo/YAP signaling pathway. Treatment with Cant suppressed YAP expression and phosphorylation on serine 127 and serine 397 while enhancing LATS1 and MST1 levels, both being important upstream regulators of YAP. Moreover, YAP-specific siRNA or YAP inhibition significantly inhibited wound healing as well as the migration and invasion rate of FLS cells, an impact similar to Cant treatment. Meanwhile, the over-expression of YAP significantly reversed the Cant-induced decline in RA-FLS cell migration and invasion, indicating that YAP was required in the inhibitory effect of Cant on the migration and invasion of RA-FLS cells. Additionally, supplementation of MMP1, but not MMP3, in culture supernatants significantly reversed the inhibitory effect of Cant on RA-FLS cell invasion. Our data collectively demonstrated that Cant may suppress RA-FLS migration and invasion by inhibiting the production of MMP1 via inhibiting the YAP signaling pathway, suggesting a potential of Cant for the further development of anti-RA drugs. Full article
(This article belongs to the Special Issue Drug Candidates for the Treatment of Immune Disease 2023)
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Review

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18 pages, 945 KiB  
Review
Emerging Pharmaceutical Therapies to Address the Inadequacy of a Gluten-Free Diet for Celiac Disease
by Martina Crepaldi, Michela Palo, Daria Maniero, Luisa Bertin, Edoardo Vincenzo Savarino, Robert P. Anderson and Fabiana Zingone
Pharmaceuticals 2024, 17(1), 4; https://doi.org/10.3390/ph17010004 - 20 Dec 2023
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Abstract
Celiac disease (CeD) is a chronic autoimmune disorder triggered by the ingestion of gluten, affecting around 1% of the global population. It is a multifactorial disease involving both genetics and environmental factors. Nowadays, the only available treatment for CeD is a life-long gluten-free [...] Read more.
Celiac disease (CeD) is a chronic autoimmune disorder triggered by the ingestion of gluten, affecting around 1% of the global population. It is a multifactorial disease involving both genetics and environmental factors. Nowadays, the only available treatment for CeD is a life-long gluten-free diet (GFD), which can cause a significant burden for patients, since symptoms and mucosal injury can persist despite apparent compliance with a GFD. This could also lead to psychological consequences and affect the quality of life of these patients. Thankfully, recent advances in understanding the pathogenesis of CeD and the availability of various targets have made it feasible to explore pharmaceutical treatments specific to CeD. Recently, the FDA has highlighted the unmet needs of adult patients on a GFD who experience ongoing symptoms attributed to CeD and also show persistent duodenal villous atrophy. This review will outline the limitations of a GFD, describe the targets of potential novel treatment of CeD and provide an overview of the primary clinical trials involving oral and injectable agents for a non-dietary treatment of CeD. Full article
(This article belongs to the Special Issue Drug Candidates for the Treatment of Immune Disease 2023)
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20 pages, 1620 KiB  
Review
Pharmacological and Electroceutical Targeting of the Cholinergic Anti-Inflammatory Pathway in Autoimmune Diseases
by Moncef Zouali
Pharmaceuticals 2023, 16(8), 1089; https://doi.org/10.3390/ph16081089 - 31 Jul 2023
Cited by 2 | Viewed by 1398
Abstract
Continuous dialogue between the immune system and the brain plays a key homeostatic role in various immune responses to environmental cues. Several functions are under the control of the vagus nerve-based inflammatory reflex, a physiological mechanism through which nerve signals regulate immune functions. [...] Read more.
Continuous dialogue between the immune system and the brain plays a key homeostatic role in various immune responses to environmental cues. Several functions are under the control of the vagus nerve-based inflammatory reflex, a physiological mechanism through which nerve signals regulate immune functions. In the cholinergic anti-inflammatory pathway, the vagus nerve, its pivotal neurotransmitter acetylcholine, together with the corresponding receptors play a key role in modulating the immune response of mammals. Through communications of peripheral nerves with immune cells, it modulates proliferation and differentiation activities of various immune cell subsets. As a result, this pathway represents a potential target for treating autoimmune diseases characterized by overt inflammation and a decrease in vagal tone. Consistently, converging observations made in both animal models and clinical trials revealed that targeting the cholinergic anti-inflammatory pathway using pharmacologic approaches can provide beneficial effects. In parallel, bioelectronic medicine has recently emerged as an alternative approach to managing systemic inflammation. In several studies, nerve electrostimulation was reported to be clinically relevant in reducing chronic inflammation in autoimmune diseases, including rheumatoid arthritis and diabetes. In the future, these new approaches could represent a major therapeutic strategy for autoimmune and inflammatory diseases. Full article
(This article belongs to the Special Issue Drug Candidates for the Treatment of Immune Disease 2023)
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