SAR443809: a selective inhibitor of the complement alternative pathway, targeting complement factor Bb.

Dysregulated activation of the complement system is implicated in the onset or progression of several diseases. Most clinical-stage complement inhibitors target the inactive complement proteins present at high concentrations in plasma, which increases target-mediated drug disposition and necessitates high drug levels to sustain therapeutic inhibition. Furthermore, many efforts are aimed at inhibiting only terminal pathway activity, which leaves opsonin-mediated effector functions intact. We describe the discovery of SAR443809, a specific inhibitor of the alternative pathway C3/C5 convertase (C3bBb). SAR443809 selectively binds to the activated form of factor B (factor Bb) and inhibits alternative pathway activity by blocking the cleavage of C3, leaving the initiation of classical and lectin complement pathways unaffected. Ex vivo experiments with patient-derived paroxysmal nocturnal hemoglobinuria erythrocytes show that, although terminal pathway inhibition via C5 blockade can effectively inhibit hemolysis, proximal complement inhibition with SAR443809 inhibits both hemolysis and C3b deposition, abrogating the propensity for extravascular hemolysis. Finally, intravenous and subcutaneous administration of the antibody in nonhuman primates demonstrated sustained inhibition of complement activity for several weeks after injection. Overall, SAR443809 shows strong potential for treatment of alternative pathway-mediated disorders.

Nek2 Kinase Signaling in Malaria, Bone, Immune and Kidney Disorders to Metastatic Cancers and Drug Resistance: Progress on Nek2 Inhibitor Development.

Cell cycle kinases represent an important component of the cell machinery that controls signal transduction involved in cell proliferation, growth, and differentiation. Nek2 is a mitotic Ser/Thr kinase that localizes predominantly to centrosomes and kinetochores and orchestrates centrosome disjunction and faithful chromosomal segregation. Its activity is tightly regulated during the cell cycle with the help of other kinases and phosphatases and via proteasomal degradation. Increased levels of Nek2 kinase can promote centrosome amplification (CA), mitotic defects, chromosome instability (CIN), tumor growth, and cancer metastasis. While it remains a highly attractive target for the development of anti-cancer therapeutics, several new roles of the Nek2 enzyme have recently emerged: these include drug resistance, bone, ciliopathies, immune and kidney diseases, and parasitic diseases such as malaria. Therefore, Nek2 is at the interface of multiple cellular processes and can influence numerous cellular signaling networks. Herein, we provide a critical overview of Nek2 kinase biology and discuss the signaling roles it plays in both normal and diseased human physiology. While the majority of research efforts over the last two decades have focused on the roles of Nek2 kinase in tumor development and cancer metastasis, the signaling mechanisms involving the key players associated with several other notable human diseases are highlighted here. We summarize the efforts made so far to develop Nek2 inhibitory small molecules, illustrate their action modalities, and provide our opinion on the future of Nek2-targeted therapeutics. It is anticipated that the functional inhibition of Nek2 kinase will be a key strategy going forward in drug development, with applications across multiple human diseases.

Structural studies of full-length receptor tyrosine kinases and their implications for drug design.

Receptor tyrosine kinases (RTKs) are important drug targets for cancer and immunological disorders. Crystal structures of individual RTK domains have contributed greatly to the structure-based drug design of clinically used drugs. Low-resolution structures from electron microscopy are now available for the RTKs, EGFR, PDGFR, and Kit. However, there are still no high-resolution structures of full-length RTKs due to the technical challenges of working with these complex, membrane proteins. Here, we review what has been learned from structural studies of these three RTKs regarding their mechanisms of ligand binding, activation, oligomerization, and inhibition. We discuss the implications for drug design. More structural data on full-length RTKs may facilitate the discovery of druggable sites and drugs with improved specificity and effectiveness against resistant mutants.

RHO GTPases: from new partners to complex immune syndromes.

Ras homology (RHO) GTPases are signalling proteins that have crucial roles in triggering multiple immune functions. Through their interactions with a broad range of effectors and kinases, they regulate cytoskeletal dynamics, cell polarity and the trafficking and proliferation of immune cells. The activity and localization of RHO GTPases are highly controlled by classical families of regulators that share consensus motifs. In this Review, we describe the recent discovery of atypical modulators and partners of RHO GTPases, which bring an additional layer of regulation and plasticity to the control of RHO GTPase activities in the immune system. Furthermore, the development of large-scale genetic screening has now enabled researchers to identify dysregulation of RHO GTPase signalling pathways as a cause of many immune system-related diseases. We discuss the mutations that have been identified in RHO GTPases and their signalling circuits in patients with rare diseases. The discoveries of new RHO GTPase partners and genetic mutations in RHO GTPase signalling hubs have uncovered unsuspected layers of crosstalk with other signalling pathways and may provide novel therapeutic opportunities for patients affected by complex immune or broader syndromes.

Venoarterial extracorporeal membrane oxygenation induces early immune alterations.

BACKGROUND: Venoarterial extracorporeal membrane oxygenation (VA-ECMO) provides heart mechanical support in critically ill patients with cardiogenic shock. Despite important progresses in the management of patients under VA-ECMO, acquired infections remain extremely frequent and increase mortality rate. Since immune dysfunctions have been described in both critically ill patients and after surgery with cardiopulmonary bypass, VA-ECMO initiation may be responsible for immune alterations that may expose patients to nosocomial infections (NI). Therefore, in this prospective study, we aimed to study immune alterations induced within the first days by VA-ECMO initiation. METHODS: We studied immune alterations induced by VA-ECMO initiation using cytometry analysis to characterize immune cell changes and enzyme-linked immunosorbent assay (ELISA) to explore plasma cytokine levels. To analyze specific changes induced by VA-ECMO initiation, nine patients under VA-ECMO (VA-ECMO patients) were compared to nine patients with cardiogenic shock (control patients). RESULTS: Baseline immune parameters were similar between the two groups. VA-ECMO was associated with a significant increase in circulating immature neutrophils with a significant decrease in C5a receptor expression. Furthermore, we found that VA-ECMO initiation was followed by lymphocyte dysfunction along with myeloid-derived suppressor cells (MDSC) expansion. ELISA analysis revealed that VA-ECMO initiation was followed by an increase in pro-inflammatory cytokines such as IL-6, IL-8 and TNF-α along with IL-10, a highly immunosuppressive cytokine. CONCLUSION: VA-ECMO is associated with early immune changes that may be responsible for innate and adaptive immune alterations that could confer an increased risk of infection.

Cellular S-denitrosylases: Potential role and interplay of Thioredoxin, TRP14, and Glutaredoxin systems in thiol-dependent protein denitrosylation.

Nitric Oxide is a very well known gaseous second messenger molecule and vasorelaxant agent involved in a variety of signaling in the body such as neurotransmission, ion channel modulation, and inflammation modulation. However, it's reversible covalent attachment to thiol groups of cysteine residues under nitrosative stress leading to aberrant protein S-nitrosylation (PSNO) has been reported in several pathological conditions in the body stemming from neurodegenerative diseases, cancer, cardiovascular system, and immune system disorders. In the cell, PSNOs are partly unstable and transit to a more stable disulfide state serving as an intermediate step towards disulfide formation thus eliciting the biological response. Scientists have identified several cellular thiol-dependent disulfide reductases that have the intrinsic capability to reverse the modification by reducing the stable disulfides formed in PSNOs and thereby rescue S-nitrosylation-induced altered proteins. The physiological roles of these major cellular ubiquitous S-denitrosylases and their probable implementations have not been fully explored. Gaining knowledge from current research and development this review provides a deeper insight into understanding the interplay and role of the major ubiquitous S-denitrosylases in maintaining cellular redox homeostasis. This review umbrellas the mechanism of Thioredoxin, TRP14, and Glutaredoxin systems and highlights their substrates specificities at different cellular conditions, physiological roles, and importance in diseased conditions that would allow researchers to investigate effective therapeutic interventions for nitrosative stress-related diseases and disorders.

Development of JAK inhibitors for the treatment of immune-mediated diseases: kinase-targeted inhibitors and pseudokinase-targeted inhibitors.

JAKs are a family of intracellular tyrosine kinases consisting of four members, JAK1, JAK2, JAK3, and TYK2. They are key components of the JAK-STAT pathway that transmit signals of many cytokines involved in the pathogenesis of numerous immune-mediated diseases and have been major molecular targets in developing new drugs for the treatment of such diseases. Some small-molecule inhibitors of JAKs have been approved by the FDA for rheumatoid arthritis, psoriatic arthritis, and inflammatory bowel disease. Now, newer JAK inhibitors with isoform-selectivity among the four different JAKs are being developed, with the aim of improving clinical outcomes compared with earlier developed drugs with pan-JAK inhibition. Most of these selective inhibitors target the kinase domains of JAKs, functioning through the traditional inhibition mode of kinases; but recently those that target their pseudokinase domains, allosterically inhibiting the enzymes, have been under development. In this review, key characteristics, efficacy, and safety of FDA-approved and representative drugs in late stages of development are briefly described in order to provide clinical implications with respect to JAK inhibitor selectivity and future development perspectives. The recent development of pseudokinase-targeted inhibitors of JAKs is also included.

Drugging the Phosphoinositide 3-Kinase (PI3K) and Phosphatidylinositol 4-Kinase (PI4K) Family of Enzymes for Treatment of Cancer, Immune Disorders, and Viral/Parasitic Infections.

The lipid kinases that generate the lipid signalling phosphoinositides have been established as fundamental signalling enzymes that control numerous aspects of how cells respond to their extracellular environment. In addition, they play critical roles in regulating membrane trafficking and lipid transport within the cell. The class I phosphoinositide kinases which generate the critical lipid signal PIP3 are hyperactivated in numerous human pathologies including cancer, overgrowth syndromes, and primary immunodeficiencies. The type III phosphatidylinositol 4-kinase beta isoform (PI4KB), which are evolutionarily similar to the class I PI3Ks, have been found to be essential host factors mediating the replication of numerous devastating pathogenic viruses. Finally, targeting the parasite variant of PI4KB has been established as one of the most promising strategies for the development of anti-malarial and anti-cryptosporidium strategies. Therefore, the development of targeted isoform selective inhibitors for these enzymes are of paramount importance. The first generation of PI3K inhibitors have recently been clinically approved for a number of different cancers, highlighting their therapeutic value. This review will examine the history of the class I PI3Ks, and the type III PI4Ks, their relevance to human disease, and the structural basis for their regulation and inhibition by potent and selective inhibitors.

Arginase as a Potential Biomarker of Disease Progression: A Molecular Imaging Perspective.

Arginase is a widely known enzyme of the urea cycle that catalyzes the hydrolysis of L-arginine to L-ornithine and urea. The action of arginase goes beyond the boundaries of hepatic ureogenic function, being widespread through most tissues. Two arginase isoforms coexist, the type I (Arg1) predominantly expressed in the liver and the type II (Arg2) expressed throughout extrahepatic tissues. By producing L-ornithine while competing with nitric oxide synthase (NOS) for the same substrate (L-arginine), arginase can influence the endogenous levels of polyamines, proline, and NO•. Several pathophysiological processes may deregulate arginase/NOS balance, disturbing the homeostasis and functionality of the organism. Upregulated arginase expression is associated with several pathological processes that can range from cardiovascular, immune-mediated, and tumorigenic conditions to neurodegenerative disorders. Thus, arginase is a potential biomarker of disease progression and severity and has recently been the subject of research studies regarding the therapeutic efficacy of arginase inhibitors. This review gives a comprehensive overview of the pathophysiological role of arginase and the current state of development of arginase inhibitors, discussing the potential of arginase as a molecular imaging biomarker and stimulating the development of novel specific and high-affinity arginase imaging probes.

Potential role of diacylglycerol kinases in immune-mediated diseases.

The mechanism promoting exacerbated immune responses in allergy and autoimmunity as well as those blunting the immune control of cancer cells are of primary interest in medicine. Diacylglycerol kinases (DGKs) are key modulators of signal transduction, which blunt diacylglycerol (DAG) signals and produce phosphatidic acid (PA). By modulating lipid second messengers, DGK modulate the activity of downstream signaling proteins, vesicle trafficking and membrane shape. The biological role of the DGK α and ζ isoforms in immune cells differentiation and effector function was subjected to in deep investigations. DGK α and ζ resulted in negatively regulating synergistic way basal and receptor induced DAG signals in T cells as well as leukocytes. In this way, they contributed to keep under control the immune response but also downmodulate immune response against tumors. Alteration in DGKα activity is also implicated in the pathogenesis of genetic perturbations of the immune function such as the X-linked lymphoproliferative disease 1 and localized juvenile periodontitis. These findings suggested a participation of DGK to the pathogenetic mechanisms underlying several immune-mediated diseases and prompted several researches aiming to target DGK with pharmacologic and molecular strategies. Those findings are discussed inhere together with experimental applications in tumors as well as in other immune-mediated diseases such as asthma.

Roles of aminoacyl-tRNA synthetases in immune regulation and immune diseases.

Aminoacyl-tRNA synthetases (ARSs) play a vital role in protein synthesis by linking amino acids to their cognate transfer RNAs (tRNAs). This typical function has been well recognized over the past few decades. However, accumulating evidence reveals that ARSs are involved in a wide range of physiological and pathological processes apart from translation. Strikingly, certain ARSs are closely related to different types of immune responses. In this review, we address the infection and immune responses induced by pathogen ARSs, as well as the potential anti-infective compounds that target pathogen ARSs. Meanwhile, we describe the functional mechanisms of ARSs in the development of immune cells. In addition, we focus on the roles of ARSs in certain immune diseases, such as autoimmune diseases, infectious diseases, and tumor immunity. Although our knowledge of ARSs in the immunological context is still in its infancy, research in this field may provide new ideas for the treatment of immune-related diseases.

Kinase Inhibitors for the Treatment of Immunological Disorders: Recent Advances.

Small molecule inhibitors targeting autoimmune and inflammatory processes have been an area of intense focus within academia and industry. Much of this work has been aimed at key kinases operating as central nodes in inflammatory signaling pathways. While this focus has led to over 30 FDA-approved small molecule kinase inhibitors, only one is currently approved for autoimmune and inflammatory diseases. Despite this lack of success, there remains tremendous reason for excitement. Our growing understanding of the biology involved in the inflammatory response, the factors that lead to safer small molecule kinase inhibitors, and the availability of selective tool molecules for interrogating specific nodes and pathways are all pushing the field forward. This article focuses on recent developments requiring novel approaches to create safe and effective small molecule kinase inhibitors and where further work is needed to realize the promise of small molecule kinase inhibitors for patient benefit.

The regulation effect of AMPK in immune related diseases.

AMP-activated protein kinase (AMPK) is a sensor of cellular energy status that plays a key role in energetic metabolism regulation. Metabolic changes in immune cells, such as dendritic cell (DC), macrophages, neutrophils and lymphocytes that participate in the signal directed programs that promote or inhibit immune mediated diseases, including cancer, atherosclerosis and inflammatory diseases. Multiple pathogenic mechanisms are involved in the initiation and progression of disease, and many pathways have been uncovered. The mechanistic overlap in the metabolic changes and inflammation could indicate that some of the targets they have are in common, whereas AMPK could be useful in treatment of both disorders. The insight into identification of AMPK responsible for specific immune regulation, anti-inflammatory actions and understanding of the underlying molecular mechanism will promote the generation of novel AMPK activators, and provide novel therapy strategy.

AID Biology: A pathological and clinical perspective.

Activation-induced cytidine deaminase (AID), primarily expressed in activated mature B lymphocytes in germinal centers, is the key factor in adaptive immune response against foreign antigens. AID is responsible for producing high-affinity and high-specificity antibodies against an infectious agent, through the physiological DNA alteration processes of antibody genes by somatic hypermutation (SHM) and class-switch recombination (CSR) and functions by deaminating deoxycytidines (dC) to deoxyuridines (dU), thereby introducing point mutations and double-stranded chromosomal breaks (DSBs). The beneficial physiological role of AID in antibody diversification is outweighed by its detrimental role in the genesis of several chronic immune diseases, under non-physiological conditions. This review offers a comprehensive and better understanding of AID biology and its pathological aspects, as well as addresses the challenges involved in AID-related cancer therapeutics, based on various recent advances and evidence available in the literature till date. In this article, we discuss ways through which our interpretation of AID biology may reflect upon novel clinical insights, which could be successfully translated into designing clinical trials and improving patient prognosis and disease management.

The dihydroorotate dehydrogenases: Past and present.

The flavoenzyme dihydroorotate dehydrogenase catalyzes the stereoselective oxidation of (S)-dihydroorotate to orotate in the fourth of the six conserved enzymatic reactions involved in the de novo pyrimidine biosynthetic pathway. Inhibition of pyrimidine metabolism by selectively targeting DHODHs has been exploited in the development of new therapies against cancer, immunological disorders, bacterial and viral infections, and parasitic diseases. Through a chronological narrative, this review summarizes the efforts of the scientific community to achieve our current understanding of structural and biochemical properties of DHODHs. It also attempts to describe the latest advances in medicinal chemistry for therapeutic development based on the selective inhibition of DHODH, including an overview of the experimental techniques used for ligand screening during the process of drug discovery.

The Roles of the Secreted Phospholipase A2 Gene Family in Immunology.

Within the phospholipase A2 (PLA2) family that hydrolyzes phospholipids to yield fatty acids and lysophospholipids, secreted PLA2 (sPLA2) enzymes comprise the largest group containing 11 isoforms in mammals. Individual sPLA2s exhibit unique tissue or cellular distributions and enzymatic properties, suggesting their distinct biological roles. Although PLA2 enzymes, particularly cytosolic PLA2 (cPLA2α), have long been implicated in inflammation by driving arachidonic acid metabolism, the precise biological roles of sPLA2s have remained a mystery over the last few decades. Recent studies employing mice gene-manipulated for individual sPLA2s, in combination with mass spectrometric lipidomics to identify their target substrates and products in vivo, have revealed their roles in diverse biological events, including immunity and associated disorders, through lipid mediator-dependent or -independent processes in given microenvironments. In this review, we summarize our current knowledge of the roles of sPLA2s in various immune responses and associated diseases.