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The Development of Improved Therapeutics through a Glycan- “Designer” Approach
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Other very interesting from the perspective of medicinal chemistry glycan groups (that should be rather avoided or carefully evaluated prior to usage) are sialic acids (Sias). Sialic acids are negatively charged, 9-carbon chain backbone monosaccharides, abundant in human cells and tissues. Their role ranges from cellular processes, regeneration to regulation of immune system. The key enzyme in the synthesis of sialic acids in human body is GNE (UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine-kinase. Sialic acids are one of the most diverse glycans. The variety arises from diverse α-linkages between second carbon C-2 of the sialic acids and underlying sugars. The variety of natural modifications adds up to a secondary level of their diversity. The combinations of different glycosidic linkages with multitude of possible modifications (e.g., Neu5Ac, Neu5Gc, addition of hydroxyl groups on C-4, C7, C-8, or C9) generate huge variety among sialic acids and account to distinctive glycocode of different cell types. Sialic acids modifications were linked to particular types of malignancies; for example, there is an association of N-glycolyl-neuraminic acid (Neu5Gc) prevalence on cancer tissues, yielding an inflammatory response (Pearce and Laubli, 2016). Some of the sialic acids in conjugation with highly immunogenic proteins/peptides are explored for their cancer protective vaccine application. Research in the field of sialic acids and their interaction with Siglec receptors could open many new ideas on immune regulation and cell signaling.
Glycan-Based Nanocarriers in Drug Delivery
Published in Raj K. Keservani, Anil K. Sharma, Rajesh K. Kesharwani, Drug Delivery Approaches and Nanosystems, 2017
Songul Yasar Yildiz, Merve Erginer, Tuba Demirci, Juergen Hemberger, Ebru Toksoy Oner
Glycans are not only used for functionalization of the nanocarriers but also used for construction of those nano-sized devices/materials for biomedical applications since glycans play numerous roles in organisms from immunogenity to cell recognition, communications and so on. Many glycans play a role in different parts of the homeostatic mechanism. For instance sialic acid, mainly bound to glycoproteins is essential for the communication and recognition with the immune system. It is known that erythrocytes without sialic acid on the surface are removed rapidly from the blood by the immune system. Another monosaccharide, mannose, plays a crucial role in protein glycosylation. Mannose binding C-type lectin proteins are important for cell surface recognition and communication. Studies with mannose generally focus on cell surface targeting. Galactose is essential for cell targeting or blood type detection due to antigen structure. Hyaluronic acid is a common glycan for vertebrate tissues but is mostly found in connective tissues and body fluids with many functions like lubrication, plasma protein regulation, filtration, homeostasis of the water. Furthermore rhamnose which is generally found in bacteria and higher organisms such as plants plays important roles in cell survival.
A human pericardium biopolymeric scaffold for autologous heart valve tissue engineering: cellular and extracellular matrix structure and biomechanical properties in comparison with a normal aortic heart valve
Published in Journal of Biomaterials Science, Polymer Edition, 2018
Frantisek Straka, David Schornik, Jaroslav Masin, Elena Filova, Tomas Mirejovsky, Zuzana Burdikova, Zdenek Svindrych, Hynek Chlup, Lukas Horny, Matej Daniel, Jiri Machac, Jelena Skibová, Jan Pirk, Lucie Bacakova
The changes in the mechanical behavior and in the structural properties of decellularized heart valve leaflets may also have a negative impact on the durability of xenogeneic heart valve prostheses [80]. In addition, remnant cellular components (such as DNA, mitochondria, membrane lipids, and cytosolic proteins) can also elicit an adverse inflammatory response and inhibit constructive remodeling, if they are not adequately removed [80]. There is also an association between macrophage phenotype (a shift in macrophage phenotype predominance from M1 to M2) and remodeling outcome [80]. Several antigens are involved in the human immune response to xenogeneic heart valve tissue, and glutaraldehyde fixation cannot sufficiently eliminate or inactivate these foreign antigens [81]. It was confirmed that the immune response in patients towards glutaraldehyde-fixed porcine heart valves is induced by porcine proteins albumin, collagen 6A1, and also αGal epitopes (α 1,3 galactose modifications) [82]. However, there are also other non-Gal carbohydrate antigens in xenogeneic tissues, e.g. non-acid and acid glycosphingolipids. Two common sialic acids in mammals, N-acetylneuraminic acid (Neu5Ac) and its hydroxylated form N-glycolylneuraminic acid (Neu5Gc), have been described in bioprosthetic heart valves [64,65]. These xeno-antigens were recognized by human anti-Neu5Gc IgG, which supports their immunogenic nature and may play a role in valve deterioration within human patients [83,84]. Magnetic resonance imaging (MRI) and a histologocal evaluation revealed a high frequency of in vivo graft failure early after implantation, due to inflammation and fibrosis of Matrix P (a decelularized porcine graft) tissue-engineered pulmonary valves (TEPV) [85]. Surgical or transcatheter TEPV replacement was needed in 52% of patients 19 months after Matrix P TEPV implantation [85].
‘Borono-lectin’ based engineering as a versatile platform for biomedical applications
Published in Science and Technology of Advanced Materials, 2018
Akira Matsumoto, Yuji Miyahara
Glycosylations, or the alternations of the glycoforms, are dynamic and stage-specific processes related to both normal and pathological events including development, differentiation, infection, genetic disorders and cancers [50–54]. However, the precise roles of glycans remain to be completely elucidated largely due to its tremendous diversity in structure. Sialic acids (SA or N-acetylneuraminic acid) is a family of sugars that constitutes a significant proportion of glycan structures. Given their outermost arrangement and uniquely anionic polarity, it mediates a variety of physiological and pathological cell processes, and thus can provide an accessible ‘code’ to tell the state of glycans in the context of cellular events. For example, sialylation is typically altered in cancers; increased expression of sialylated glycans is a common manifestation of cancer progression, poor prognosis and higher metastatic potential [55–57]. Therefore, determination of the glycan SA is relevant to diagnosis of these cancerous conditions. Furthermore, SA-specific molecular recognition leads to capability of targeting therapeutic agents to highly sialylated epitopes or tumor cells. BA-related chemistry does provide solutions for these challenges. A capability of BA of specifically binding with SA among other glycan-related sugars had been clarified based on nuclear magnetic resonance (NMR) studies; the origin of the SA-specificity has been attributed to multiple metastable binding sites in the complex along with intramolecular stabilization effect involving B-N or B-O interactions [58,59]. Taking advantage of this finding, we have reported a BA-based potentiometric detection technique for SA as a new platform for noninvasive and label-free cytology [60,61]. A PBA modified self-assembled monolayer was immobilized on the surface of a gold electrode, which was then used as an extended gate of a field effect transistor (FET). The specific binding between negatively charged SA and PBA led to a change in the surface potential of the FET. The resultant in situ chemical-to-electrical signal-transduction mode proved an efficient means to quantify the cell-surface expressed SA on a label-free and real-time format (Figure 2). It was able to distinguish the SA alternations on the surface of erythrocytes [56] as well as metastatic murine melanoma cells (B16-F10) [57], simply by placing the known-count living cell suspensions onto the electrode, each relevant to the diagnosis of diabetes and tumor metastatic potential.