We have focused on a molecule named podoplanin (PDPN) as a therapeutic target of malignant brain tumors. PDPN is a type I transmembrane mucin-like glycoprotein that is abundant in several solid tumors including squamous cell carcinoma, malignant mesothelioma, Kaposi sarcoma, angiosarcoma, testicular seminoma, and brain tumors. The expression level of PDPN is reported to increase as tumor malignancy increases. The side effects of currently available treatments can be avoided or mitigated if new measures are developed that only kill PDPN-expressing tumor cells. ...and more
Sialic acid is a “uronic acid”, sugar with a carboxyl group as an acidic functional group. While many monosaccharides in glycans in the body are pentoses and hexoses, sialic acid is a nonose and plays various and important physiological roles. In the author’s opinion, sialic acid must be a distinguished from other sugars. Regarding the chemical synthesis of glycans, the presence of sialic acid in a glycan dramatically increases the difficulty of its synthesis. Because of its unique structure, sialic acid markedly decreases the success rate of glycosidation. A fundamental solution to this problem has been sought for more than half a century. Recently, our group successfully developed one approach to solving this problem. In this article, I will outline this approach. ...and more
The extracellular matrix (ECM) plays a central role in brain homeostasis. Earlier studies have shown that the ECM is involved in the control of neuronal and glial functions through regulation of growth factors, neurotrophic factors, and neurotransmitters. It has also been shown that ECM is involved in embryonic neurogenesis and axonal outgrowth during brain development. Interestingly, recent studies have suggested that the ECM constitutes a microenvironment called the “neurogenic niche” in the dentate gyrus of the adult hippocampus, where the ECM may be involved in the proliferation and differentiation of neural stem cells (NSCs) and neuronal progenitor cells (NPCs) into newborn granule cells (NGCs) . We have reported that chondroitin sulfate proteoglycan (CSPG), one of the major molecules of the brain ECM, may improve cognitive function via promotion of adult neurogenesis in the hippocampus. This perspective outlines that CSPG may work as a molecular target for dementia treatment. ...and more
Many viral pathogens utilize heparan sulfate as attachment factors, which facilitates the initial interaction with host cells. We recently identified 3'-Phosphoadenosine 5'-Phosphosulfate Synthase 1（PAPSS1）as a host factor for herpes simplex virus type 1 (HSV-1) infection by a genome-wide loss-of function CRISPR screen1. The Knockout (KO) of PAPSS1 reduced heparan sulfate expression. Here, I would like to introduce and discuss the role of heparan sulfate on viral infection. ...and more
Ribitol phosphate is a sugar alcohol phosphate, which is known as a component of teichoic acid in bacterial cell walls. In 2016, ribitol phosphate was found in vertebrate cells as a sugar chain component of dystroglycan. At the same time, a group of enzymes involved in the biosynthesis of ribitol phosphate was also identified, and mutations in the genes encoding these enzymes are responsible for several types of muscular dystrophy. As the mechanism of ribitol phosphate modification is revealed, the development of therapies for ribitol phosphate-defective muscular dystrophy is heating up. This article describes the history of ribitol phosphate discovery and the therapeutic strategies currently proposed. ...and more
IgG activates FcγRs and the complement system while intravenous immunoglobulin (IVIG) consisting of plasma IgG exerts anti-inflammatory effects in the treatment of autoimmune diseases. Although IVIG has been used for >40 years as a treatment option for certain autoimmune disorders, its mechanism of action (MOA) remains unsolved. Recently developed chemo-enzymatic glycoengineering approach allows for remodeling of the Fc glycans of polyclonal IgG. We prepared fucosylated or nonfucosylated plasma IgG glycoforms having 2 sialic acids, 2 galactose, or 0 galactose at the nonreducing ends of the Fc glycans to investigate their anti-inflammatory activity. We have demonstrated that the galactosylated, nonfucosylated [(G2)2] glycoform has the highest affinity for FcγRIIIa and potency to inhibit antibody-dependent cellular cytotoxicity (ADCC) activity of immune cells. As the (G2)2 glycoform is a component of IVIG, glycoengineered IVIG consisting of the (G2)2 glycoform alone may be a potential next-generation antibody drug. This review outlines our current understanding of the role of IgG-Fc glycan in MOA of IVIG. ...and more
The use of antibody drugs has been spreading rapidly because of their excellent pharmacological effects and the recent advances in antibody humanization technology and biologic production technology. Currently, a large number of antibody drugs are being marketed as block busters; as such, antibody drugs may be described as occupying an established position in the pharmaceutical industry. On the other hand, suitable targets for disease-specific treatments are increasingly being depleted; a key step in antibody drug development is the discovery of new-generation target antigens.
We are working on discovering specific cancer antigens for malignant mesothelioma, an intractable cancer. Mesothelioma has long been an “indistinct” cancer as it lacks good cancer markers and hence is quite difficult to diagnose pathologically. Recognizing a new protein antigen encompassing a “glycopeptide region with mesothelioma-specific glycosylation,” our anti-mesothelioma antibody is highly promising as a new antibody drug seed expected to contribute to the diagnosis and treatment of mesothelioma, and as a drug discovery seed for targeting glycans. This article provides a historical overview of the research and development, and future prospects for clinical application of this antibody.
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To understand the biological processes mediated by various glycoforms of glycoproteins, the preparation of homogeneous glycoproteins is essential for performing extensive biological experiments. Recently we found that diacyl disulfide coupling (DDC) between glycosyl asparagine and peptide yielded glycopeptides chemoselectively. DDC enabled us to develop a new glycoprotein synthesis method, “the chemical glycan insertion strategy,” which can insert glycosyl asparagine between the N- and C- termini of two unprotected peptides. In our design concept, fewer steps are needed to generate glycoproteins. Herein, I will introduce the latest strategy of glycoproteins synthesis by chemical insertion. ...and more
Heparan sulfate (HS) is present as a component of proteoglycans on cell surfaces and in the extracellular matrix in most animal species including Hydra, Caenorhabditis, Drosophila, and humans. HS chains are structurally heterogeneous, being composed of densely sulfated regions, or sulfated domains, connected by mostly nonsulfated and N-acetyl-rich regions. HS regulates various physiological processes by the interaction with numerous proteins such as growth factors, morphogens, cytokines, enzymes, and extracellular matrix proteins. The binding specificity of HS for each functional protein is thought to be dependent on the structure of the sulfated domain. ...and more
Cardiovascular and cerebrovascular diseases such as myocardial and cerebral infarction are caused by atherosclerotic disease1. Atherosclerotic diseases are the cause of approximately 25% of deaths in Japan, and constitute a major threat to the Japanese population, so there is a very high societal demand for these diseases to be defeated.
Treatment of atherosclerosis has previously focused on controlling the risk factors for cardiovascular disease development, represented by hypertension, diabetes, dyslipidemia, etc. Various risk factors are in fact increasingly controllable with renin-angiotensin system inhibitors, statins, etc. However, taking into consideration the continuing increase in the prevalence of cardiovascular diseases, there is an urgent need to establish new treatment strategies.
The response-to-retention hypothesis has been put forward for the mechanisms of onset and progression of atherosclerosis, and has been given considerable attention2,3. Accumulation of low-density lipoprotein (LDL) cholesterol and other lipids in vascular walls is considered to be a starting point for onset of early-stage arteriosclerosis, and it has recently been suggested that the structures of chondroitin sulfate chains in the tunica intima are connected to that accumulation, with the length of the chains being particularly closely connected4.
The present authors have put forward the following hypothesis: “Accumulation of lipids can be reduced by modifying the lengths of chondroitin sulfate chains, enabling prevention of or recovery from atherosclerosis”. Studies have since been performed to test this hypothesis, and the results are summarized here. ...and more
The recent COVID-19 pandemic is caused by a new coronavirus, SARS-CoV-2, whose spike protein on its surface binds to human cells via angiotensin-converting enzyme 2 (ACE2) receptors in the initial stage of infection. In that process, the structure of the spike protein changes from a “down-form” to an “up-form”, as demonstrated by cryo-electron microscopy. Biochemical experiments have shown that the surface of the spike protein is modified by many glycans. Glycans have been considered to play a role in protection against antibodies, i.e., immune evasion; however, how they contribute to the structural changes of the spike protein remains unclear. In this paper, we describe the role of glycans as elucidated by molecular dynamics simulation of the spike protein. ...and more
Lactoferrin (LF) is a glycosaminoglycan-binding protein that functions in innate immunity, and it is expected to be useful as a biopharmaceutical product due to its effects on the body. We aim to develop novel therapeutic agents that can promote effective recovery from spinal cord injuries. Through our recent research, we discovered that LF binds to chondroitin sulfate E (CS-E), inhibiting nerve axon outgrowth and neutralizing its toxicity. We have also developed a highly functionalized neuroprotective molecule consisting of granulocyte colony-stimulating factor (G-CSF) linked to LF. This paper introduces this highly functionalized LF and discusses its glycan-binding and neuroprotective properties. ...and more
Starch, a polysaccharide composed of glucose molecules, is formed during photosynthesis by Archaeplastida and is found in staple food crops such as cereals, tubers, and beans. Starch is utilized not just for food and food additive purposes but also for industrial purposes, e.g., in the manufacture of glues and bioplastics. Starch consists of amylose and amylopectin. The primary constituent amylopectin has an orderly branched structure and its structure has an effect on the taste and physicochemical properties of starch. Starch synthase, branching enzyme, and debranching enzyme are involved in amylopectin biosynthesis, but the mechanism controlling the assembly of highly ordered structures remains to be elucidated. Understanding the mechanisms controlling amylopectin’s structure opens up the possibility of designing an amylopectin with a favorable structure and properties. The authors have clarified the mechanism controlling the length of branched chains formed by branching enzymes. In this article, we describe the problems that need to be solved in order to control the structure and properties of amylopectin and recent progress in studies on branching enzymes. The production of structure-controlled amylopectins contributes to the development of our nation by raising the level of its food self-sufficiency and helping it reach the goal of a decarbonized society. ...and more
Cellulose is a natural polysaccharide, and is functionally classified as a structural polysaccharide. Its superior strength is attributed to the fact that it is composed of multiple molecular chains, and it has a structure known as cellulose I crystal that exhibits a high crystalline modulus. The fact that such an agglomeration of polymers can be synthesized by enzymatic proteins suggests that cellulose biosynthesis is a mechanism designed to synthesize the strongest possible structure by controlling the polymer chains at ambient temperature and pressure in aqueous solvents. In comparison with the typical formation process for general-purpose polymers, which involves high temperature, high pressure, and harsh solvents, the enzyme cellulose synthase possesses an extremely sophisticated “green” mechanism for controlling polymer structure.
In this paper, I will describe efforts to reconstitute the cellulose-synthesizing activity of cellulose synthase, the mechanism of which we have been seeking to elucidate for more than 10 years. ...and more
Grafting is a technique for cultivating plants that combines the advantages of two different plant species, and it has been used as an agricultural technique since ancient times. The cell wall surrounding the plant cell is an extracellular matrix composed of multiple polysaccharides, the composition of which depends on the plant species. Grafting is thought to occur when the cell walls of two grafted plants are reconstituted at their boundaries, resulting in cell or tissue adhesion. In this article, we will introduce the mechanism of artificial plant grafting and the similarity between grafting in nature and grafting in plants, focusing on the function of digestive enzymes of cellulose, the main component of cell walls. ...and more
