scholarly journals Small Molecule Inhibitors in the Treatment of Rheumatoid Arthritis and Beyond: Latest Updates and Potential Strategy for Fighting COVID-19

Cells ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 1876
Author(s):  
Magdalena Massalska ◽  
Wlodzimierz Maslinski ◽  
Marzena Ciechomska
Keyword(s):  
Rheumatoid Arthritis ◽  
Small Molecule ◽  
Viral Entry ◽  
Small Molecule Inhibitors ◽  
Large Family ◽  
Downstream Signaling ◽  
Wide Range ◽  
Synthetic Dmards ◽  
Potential Strategy ◽  
Inflammatory Molecules

The development of biological disease-modifying antirheumatic drugs (bDMARDs) and target synthetic DMARDs (tsDMARDs), also known as small molecule inhibitors, represent a breakthrough in rheumatoid arthritis (RA) treatment. The tsDMARDs are a large family of small molecules targeting mostly the several types of kinases, which are essential in downstream signaling of pro-inflammatory molecules. This review highlights current challenges associated with the treatment of RA using small molecule inhibitors targeting intracellular JAKs/MAPKs/NF-κB/SYK-BTK signaling pathways. Indeed, we have provided the latest update on development of small molecule inhibitors, their clinical efficacy and safety as a strategy for RA treatment. On the other hand, we have highlighted the risk and adverse effects of tsDMARDs administration including, among others, infections and thromboembolism. Therefore, performance of blood tests or viral infection screening should be recommended before the tsDMARDs administration. Interestingly, recent events of SARS-CoV-2 outbreak have demonstrated the potential use of small molecule inhibitors not only in RA treatment, but also in fighting COVID-19 via blocking the viral entry, preventing of hyperimmune activation and reducing cytokine storm. Thus, small molecule inhibitors, targeting wide range of pro-inflammatory singling pathways, may find wider implications not only for the management of RA but also in the controlling of COVID-19.

scholarly journals Small molecule inhibitors of Hsp90 potently affect inflammatory disease pathways and exhibit activity in models of rheumatoid arthritis

2008 ◽  
Vol 58 (12) ◽  
pp. 3765-3775 ◽  
Author(s):  
John W. Rice ◽  
James M. Veal ◽  
R. Patrick Fadden ◽  
Amy F. Barabasz ◽  
Jeffrey M. Partridge ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Small Molecule ◽  
Inflammatory Disease ◽  
Small Molecule Inhibitors ◽  
Disease Pathways

Elucidating Protein-protein Interactions Through Computational Approaches and Designing Small Molecule Inhibitors Against them for Various Diseases

2018 ◽  
Vol 18 (20) ◽  
pp. 1719-1736 ◽  
Author(s):  
Sharanya Sarkar ◽  
Khushboo Gulati ◽  
Manikyaprabhu Kairamkonda ◽  
Amit Mishra ◽  
Krishna Mohan Poluri
Keyword(s):  
Small Molecule ◽  
Protein Interactions ◽  
Small Molecule Inhibitors ◽  
Computational Techniques ◽  
Protein Protein Interactions ◽  
Computational Tools ◽  
Computational Approaches ◽  
Protein Protein Interaction ◽  
Wide Range ◽  
Therapeutic Measures

Background: To carry out wide range of cellular functionalities, proteins often associate with one or more proteins in a phenomenon known as Protein-Protein Interaction (PPI). Experimental and computational approaches were applied on PPIs in order to determine the interacting partners, and also to understand how an abnormality in such interactions can become the principle cause of a disease. Objective: This review aims to elucidate the case studies where PPIs involved in various human diseases have been proven or validated with computational techniques, and also to elucidate how small molecule inhibitors of PPIs have been designed computationally to act as effective therapeutic measures against certain diseases. Results: Computational techniques to predict PPIs are emerging rapidly in the modern day. They not only help in predicting new PPIs, but also generate outputs that substantiate the experimentally determined results. Moreover, computation has aided in the designing of novel inhibitor molecules disrupting the PPIs. Some of them are already being tested in the clinical trials. Conclusion: This review delineated the classification of computational tools that are essential to investigate PPIs. Furthermore, the review shed light on how indispensable computational tools have become in the field of medicine to analyze the interaction networks and to design novel inhibitors efficiently against dreadful diseases in a shorter time span.

scholarly journals Identification of small molecule inhibitors of RANKL and TNF signalling as anti-inflammatory and antiresorptive agents in mice

2013 ◽  
Vol 74 (1) ◽  
pp. 220-226 ◽  
Author(s):  
Emmanuel Coste ◽  
Iain R Greig ◽  
Patrick Mollat ◽  
Lorraine Rose ◽  
Mohini Gray ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Bone Loss ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Joint Destruction ◽  
Luciferase Reporter ◽  
Collagen Induced Arthritis ◽  
Arthritis Model ◽  
Anti Inflammatory ◽  
Systemic Bone Loss

IntroductionInflammatory joint diseases such as rheumatoid arthritis are associated with local bone erosions and systemic bone loss, mediated by increased osteoclastic activity. The receptor activator of nuclear factor (NF) κB ligand (RANKL) plays a key role in mediating inflammation-induced bone loss, whereas tumour necrosis factor (TNF) plays a central role in the inflammatory process. Here we tested whether a recently identified class of small molecule inhibitors of RANKL signalling (ABD compounds) also affect TNF signalling and whether these compounds inhibit inflammation in an animal model of rheumatoid arthritis.MethodsThe inhibitory effects of the ABD compounds on TNF-induced signalling were tested in mouse macrophage cultures by western blotting and in an NFκB luciferase-reporter cell line. The anti-inflammatory effects of the compounds were tested in the mouse collagen-induced arthritis model of rheumatoid arthritis.ResultsThe ABD compounds ABD328 and ABD345 both inhibited TNF-induced activation of the NFκB pathway and the extracellular signal-regulated kinase (ERK) and Jun kinase (JNK) mitogen activated protein kinases (MAPKs). When tested in the mouse collagen-induced arthritis model of rheumatoid arthritis, the compounds suppressed inflammatory arthritis, inhibited joint destruction and prevented systemic bone loss. Furthermore, one of the compounds (ABD328) showed oral activity.ConclusionsHere we describe a novel class of small molecule compounds that inhibit both RANKL- and TNF-induced NFκB and MAPK signalling in osteoclasts and macrophages, and inflammation and bone destruction in a mouse model of rheumatoid arthritis. These novel compounds therefore represent a promising new class of treatments for inflammatory diseases, such as rheumatoid arthritis.

scholarly journals SAT0016 DEVELOPMENT OF FIBROBLAST-LIKE SYNOVIOCYTE ASSAYS FOR TARGET DISCOVERY IN RHEUMATOID ARTHRITIS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 938.1-938
Author(s):  
D. Ruelas ◽  
C. Chen ◽  
H. Truong ◽  
V. Lira ◽  
Y. Moazami ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Growth Factor ◽  
Synovial Fluid ◽  
Real Time ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Complete Inhibition ◽  
Cytokine Secretion ◽  
Target Discovery ◽  
Secretion Assay

Background:The rheumatoid arthritis (RA) synovium is characterized by an overabundance of fibroblast-like synoviocytes (FLS), which play a central role in the initiation and perpetuation of disease via multiple mechanisms.1FLS promote disease progression by producing high levels of proinflammatory factors, migrating to and invading cartilage and bone, and promoting self-proliferation and resistance to apoptosis. Our current understanding of the molecular mechanisms that govern FLS-mediated pathology in the synovial joint remains incomplete. Importantly, almost 30% of treatment-naïve early RA patients exhibit a strong fibroid phenotype that correlates with relatively poor response to disease-modifying anti-rheumatic drugs.2Yet, current therapies in RA are not directly aimed at FLS pathology, creating an opportunity for novel therapeutic target discovery.Objectives:Our aim is to develop a broad suite of screening-amenable assays in RA patient-derived FLS for the discovery of target pathways that control multiple pathological properties, including cytokine secretion, migration, and invasion.Methods:A sensitive high-throughput RA-FLS secretion assay was developed to examine the ability of small-molecule inhibitors to block the production of interleukin (IL)-6 and matrix metalloproteinase (MMP)-3 in response to stimuli. To create a physiologically relevant stimulus, a surrogate synovial fluid cocktail (composed of 12 factors) was defined and titrated for optimal concentration selection. Small-molecule inhibitors (N=170) of diverse biological pathways were screened using the full cocktail or individual stimulation (TNFα, IL-1α, or IL-17) to characterize assay performance. In addition, an FLS platelet-derived growth factor (PDGF)-mediated migration screening assay was developed using a live cell imaging system (IncuCyte) to quantify real-time FLS migration.Results:Due to the variability and limited volume of synovial fluid, we developed a surrogate synovial fluid cocktail to mimic the relevant stimulation of RA-FLS in the inflamed joint. The surrogate cocktail was composed of 12 factors: TNFα, IL-1α, IL-17, IFNγ, OSM, LIF, GM-CSF, IP-10, VEGF, PDGF, AREG, and FGF2. Individual titration of these factors demonstrated that only 3 stimulatory factors (TNFα, IL-1α, and IL-17) resulted in a robust increase of IL-6 production. Importantly, when all 12 factors were combined, a synergistic increase in IL-6 and MMP-3 production by FLS was observed. Screening results identified several reference compounds, including an inhibitor of transforming growth factor-b–activated kinase 1 (TAK1), that was previously reported to block cytokine secretion in FLS.3Treatment with this compound showed complete inhibition of IL-6 and MMP-3 secretion. In addition to the cytokine secretion assay, treatment of FLS with this TAK1 inhibitor resulted in almost complete inhibition of migration (Fig. 1).Conclusion:Novel FLS assays were developed to discover new targets and interrogate pathways involved in multiple disease-driving mechanisms of FLS in RA. In order to mimic the inflammatory environment present in the RA synovium, we developed a 12-factor surrogate synovial fluid cocktail. A synergistic release of both IL-6 and MMP-3 was demonstrated following cocktail stimulation compared to individual cytokines. This points to the important contribution that multiple factors play in the FLS pathogenic processes and will allow us to uncover pathway interactions that may not be captured with single stimuli. In addition, the development of a real-time, 96-well, imaging-based assay to interrogate FLS migration will allow us to identify targets that control this critical pathological function of FLS.References:[1] Bartok B, et al.J Immunol. 2014;192(5):2063-2070.[2] Humby F, et al.Ann Rheum Dis. 2019;78(6):761-772.[3] Jones DS, et al.Nat Chem Bio. 2017;13(1):38-45.Disclosure of Interests:Debbie Ruelas Employee of: Gilead, Chen Chen Employee of: Gilead, Hoa Truong Employee of: Gilead, Victor Lira Employee of: Gilead, Yasamin Moazami Employee of: Gilead, Kevin Currie Employee of: Gilead, Julie A. Di Paolo Employee of: Gilead, Helen Yu Employee of: Gilead, Gundula Min-Oo Employee of: Gilead

scholarly journals Peptide Inhibitors of Kv1.5: An Option for the Treatment of Atrial Fibrillation

2021 ◽  
Vol 14 (12) ◽  
pp. 1303
Author(s):  
Jesús Borrego ◽  
Adam Feher ◽  
Norbert Jost ◽  
Gyorgy Panyi ◽  
Zoltan Varga ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Amino Acid Sequences ◽  
Rational Drug Design ◽  
Drug Candidate ◽  
In Silico Docking ◽  
Rational Drug ◽  
Wide Range ◽  
Potential Therapeutic Application

The human voltage gated potassium channel Kv1.5 that conducts the IKur current is a key determinant of the atrial action potential. Its mutations have been linked to hereditary forms of atrial fibrillation (AF), and the channel is an attractive target for the management of AF. The development of IKur blockers to treat AF resulted in small molecule Kv1.5 inhibitors. The selectivity of the blocker for the target channel plays an important role in the potential therapeutic application of the drug candidate: the higher the selectivity, the lower the risk of side effects. In this respect, small molecule inhibitors of Kv1.5 are compromised due to their limited selectivity. A wide range of peptide toxins from venomous animals are targeting ion channels, including mammalian channels. These peptides usually have a much larger interacting surface with the ion channel compared to small molecule inhibitors and thus, generally confer higher selectivity to the peptide blockers. We found two peptides in the literature, which inhibited IKur: Ts6 and Osu1. Their affinity and selectivity for Kv1.5 can be improved by rational drug design in which their amino acid sequences could be modified in a targeted way guided by in silico docking experiments.

Discovery of a series of imidazopyrazine small molecule inhibitors of the kinase MAPKAPK5, that show activity using in vitro and in vivo models of rheumatoid arthritis

2012 ◽  
Vol 22 (6) ◽  
pp. 2266-2270 ◽  
Author(s):  
Martin J.I. Andrews ◽  
J. Andrew Clase ◽  
Gregory Bar ◽  
Giovanni Tricarico ◽  
Paul J. Edwards ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
In Vivo Models

scholarly journals Promiscuity and specificity of eukaryotic glycosyltransferases

2020 ◽  
Vol 48 (3) ◽  
pp. 891-900 ◽  
Author(s):  
Ansuman Biswas ◽  
Mukund Thattai
Keyword(s):  
Small Molecule ◽  
Large Family ◽  
Organic Substrates ◽  
Cellular Interactions ◽  
Structural Studies ◽  
Glycosidic Linkage ◽  
Enzyme Promiscuity ◽  
Acceptor Substrate ◽  
Wide Range ◽  
Recognition Motifs

Glycosyltransferases are a large family of enzymes responsible for covalently linking sugar monosaccharides to a variety of organic substrates. These enzymes drive the synthesis of complex oligosaccharides known as glycans, which play key roles in inter-cellular interactions across all the kingdoms of life; they also catalyze sugar attachment during the synthesis of small-molecule metabolites such as plant flavonoids. A given glycosyltransferase enzyme is typically responsible for attaching a specific donor monosaccharide, via a specific glycosidic linkage, to a specific moiety on the acceptor substrate. However these enzymes are often promiscuous, able catalyze linkages between a variety of donors and acceptors. In this review we discuss distinct classes of glycosyltransferase promiscuity, each illustrated by enzymatic examples from small-molecule or glycan synthesis. We highlight the physical causes of promiscuity, and its biochemical consequences. Structural studies of glycosyltransferases involved in glycan synthesis show that they make specific contacts with ‘recognition motifs’ that are much smaller than the full oligosaccharide substrate. There is a wide range in the sizes of glycosyltransferase recognition motifs: highly promiscuous enzymes recognize monosaccharide or disaccharide motifs across multiple oligosaccharides, while highly specific enzymes recognize large, complex motifs found on few oligosaccharides. In eukaryotes, the localization of glycosyltransferases within compartments of the Golgi apparatus may play a role in mitigating the glycan variability caused by enzyme promiscuity.

scholarly journals Identification of Novel Potential VEGFR-2 Inhibitors Using a Combination of Computational Methods for Drug Discovery

Life ◽  
2021 ◽  
Vol 11 (10) ◽  
pp. 1070
Author(s):  
Mohammad M. Al-Sanea ◽  
Garri Chilingaryan ◽  
Narek Abelyan ◽  
Arsen Sargsyan ◽  
Sargis Hovhannisyan ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Computational Methods ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Acquired Resistance ◽  
Growth Factor Receptor ◽  
Clinical Effects ◽  
Wide Range ◽  
Critical Issues ◽  
Endothelial Growth Factor

The vascular endothelial growth factor receptor 2 (VEGFR-2) is largely recognized as a potent therapeutic molecular target for the development of angiogenesis-related tumor treatment. Tumor growth, metastasis and multidrug resistance highly depends on the angiogenesis and drug discovery of the potential small molecules targeting VEGFR-2, with the potential anti-angiogenic activity being of high interest to anti-cancer research. Multiple small molecule inhibitors of the VEGFR-2 are approved for the treatment of different type of cancers, with one of the most recent, tivozanib, being approved by the FDA for the treatment of relapsed or refractory advanced renal cell carcinoma (RCC). However, the endogenous and acquired resistance of the protein, toxicity of compounds and wide range of side effects still remain critical issues, which lead to the short-term clinical effects and failure of antiangiogenic drugs. We applied a combination of computational methods and approaches for drug design and discovery with the goal of finding novel, potential and small molecule inhibitors of VEGFR2, as alternatives to the known inhibitors’ chemical scaffolds and components. From studying several of these compounds, the derivatives of pyrido[1,2-a]pyrimidin-4-one and isoindoline-1,3-dione in particular were identified.

scholarly journals Structural Basis of SARS-CoV-2– and SARS-CoV–Receptor Binding and Small-Molecule Blockers as Potential Therapeutics

2021 ◽  
Vol 61 (1) ◽  
pp. 465-493 ◽  
Author(s):  
Hariharan Sivaraman ◽  
Shi Yin Er ◽  
Yeu Khai Choong ◽  
Edem Gavor ◽  
J. Sivaraman
Keyword(s):  
Small Molecule ◽  
Receptor Binding ◽  
Viral Entry ◽  
Small Molecule Inhibitors ◽  
Therapeutic Potential ◽  
Structural Basis ◽  
Virus Receptor ◽  
Fusion Inhibitors ◽  
Human Coronaviruses ◽  
Transmembrane Serine Protease

Over the past two decades, deadly coronaviruses, with the most recent being the severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2) 2019 pandemic, have majorly challenged public health. The path for virus invasion into humans and other hosts is mediated by host–pathogen interactions, specifically virus–receptor binding. An in-depth understanding of the virus–receptor binding mechanism is a prerequisite for the discovery of vaccines, antibodies, and small-molecule inhibitors that can interrupt this interaction and prevent or cure infection. In this review, we discuss the viral entry mechanism, the known structural aspects of virus–receptor interactions (SARS-CoV-2 S/humanACE2, SARS-CoV S/humanACE2, and MERS-CoV S/humanDPP4), the key protein domains and amino acid residues involved in binding, and the small-molecule inhibitors and other drugs that have (as of June 2020) exhibited therapeutic potential. Specifically, we review the potential clinical utility of two transmembrane serine protease 2 (TMPRSS2)-targeting protease inhibitors, nafamostat mesylate and camostat mesylate, as well as two novel potent fusion inhibitors and the repurposed Ebola drug, remdesivir, which is specific to RNA-dependent RNA polymerase, against human coronaviruses, including SARS-CoV-2.

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