A szénhidrátok és konjugátumaik biológiai szerepei
Important Facts About Glycans
General 1. Glycans are the most abundant family of organic molecules on the planet. 2. The potential information content of glycans vastly exceeds that of any other class of macromolecules. 3. Every living cell on the planet is covered with a dense and complex array of glycans. These glycans form the glycocalyx in many types of cells (such as in humans) and comprise the cell wall in others (such as plants). Some cells do not have a nucleus, but all have a glycocalyx or cell wall. 4. Every molecule, cell, or organism that interacts with a cell must do so in the context of the glycocalyx or cell wall. 5. The vast majority of cellular and secreted proteins are modified with glycans, which modify, alter, and/or control their functions.
Important Facts About Glycans
Health 1. Elimination of any single major class of glycans from an organism results in death.
2. Every disease that affects humans significantly involves glycans. 3. A great majority of host-pathogen interactions involve glycans, via recognition, degradation, or molecular mimicry. 4. Most protein therapeutics must be glycosylated properly to be functionally effective. 5. Altered glycosylation is a universal feature of cancer and contributes to pathogenesis and progression.
6. Many vaccines are glycan based.
Important Facts About Glycans Sustainability 1. Glycoscience is one of the only fields that directly impacts both the pharmaceutical and energy industries. 2. The majority of solar energy trapped as cellular energy is converted to carbohydrates. 3. There are no other candidate classes of molecules that can solve our energy and materials needs. 4. Petroleum resources have finite lifetimes, but polysaccharide resources are continually being created with the sun’s energy. 5. Nitrogen fixation in plants depends on carbohydrate signaling between bacteria and plant roots.
„Leg”-ek a szénhidrátokkal kapcsolatban A Földön élő szervezetekből és az általuk termelt szerves anyagokból álló, évente újratermelődő biomassza ~105 milliárd tonna/év tömegűnek becsülhető.
Forrás: C. B. Field et al., Science, 1998, 281, 237.
(Cellulóz, hemicellulóz, kitin, keményítő, glikogén, stb.)
Szénhidrátok Lignin Egyéb
Legnagyobb tömeg
(Fehérjék, nukleinsavak, lipidek, szekunder metabolitok, stb.)
„Leg”-ek a szénhidrátokkal kapcsolatban Bélüreg glikokalix
Véredény glikokalix
http://www.anatomybox. com/tag/glycocalyx/
B. M. van den Berg et al. Circ. Res., 2003, 92, 592.
Minden élő sejt felületét oligoszacharidokból álló szénhidrát réteg (glikokalix) borítja, vagy sejtfalát szénhidrátok alkotják. Bélbolyhok glikokalixa
SEM mikrofelvétel (nagyítás: 200 000) K. Horiuchi et al. Arch. Histol. Cytol., 2005, 68, 51.
Legelterjedtebbek
A glikokalix mérete
Endothelial surface layer (ESL) vázlatos felépítése (endothelium: egyrétegű laphám, erek és savós üregek bélése)
A glikokalix néhány eleme (Sia = sziálsav (N-acetil-neuraminsav)
A prion is an infectious agent composed of protein material, that can fold in multiple, structurally distinct ways, at least one of which is transmissible to other prion proteins, leading to disease that is similar to viral infection.
A ganglioside is a glycosphingolipid with one or more sialic acids linked on the sugar chain. It modulates cell signal transduction events, and appears to concentrate in lipid rafts.
CD34 is a cell surface glycoprotein and functions as a cell-cell adhesion factor. It may also mediate the attachment of stem cells to bone marrow extracellular matrix or directly to stromal cells.
Neural cell adhesion molecule (NCAM): glycoprotein expressed on the surface of neurons, glia, skeletal muscle and natural killer cells, has a role in cell–cell adhesion, neurite outgrowth, synaptic plasticity, and learning and memory.
Glikolipidek – oligoszacharid-lipid konjugátumok Pl. az AB0(H) vércsoport antigén glikoszfingolipidek (immunológiai információ hordozók)
O-Glikoproteinek
Glikoproteinek – oligoszacharid-fehérje konjugátumok I.
Típusok
Glikoproteinek – oligoszacharid-fehérje konjugátumok II.
Biológiai szerepek The carbohydrate groups confer important properties to proteins such as • conformational stability, • protease resistance, • charge and water binding capacity, • specificities in biological recognition, • signals for targeting. Glycoproteins are essential to many basic cellular and disease processes including • molecular/cellular recognition, • intracellular sorting, • cell growth, • fertilization, • immune defense, • inflammation, • tumor metastasis, • viral replication and bacterial/parasite infection.
Glikoproteinek – oligoszacharid-fehérje konjugátumok III.
A poszttranszlációs glikozilezés jellegzetességei The post-translational glycosylation of polypeptides to form glycoproteins has the following characteristics: • Different glycoproteins from the same cell may contain different oligosaccharide structures. • An individual glycoprotein may contain multiple glycosylation sites. • An individual polypeptide usually carries several different oligosaccharide structures, many of which are found at the same glycosylation site referred to as site heterogeneity (microheterogeneity). • The oligosaccharide heterogeneity results in a set of glycosylated structures known as glycoforms with different physical and biochemical properties that may lead to functional diversity. • The oligosaccharide heterogeneity at a single glycosylation site is reproducible during a constant physiological condition. • The oligosaccharide processing is cell and tissue specific.
The oligosaccharide processing is cell and tissue specific.
Az eritropoietin glikozilezése - doppingvizsgálat Az eritropoietin (EPO) egy, a vese által termelt glikozilezett plazmafehérje, amely serkenti a csontvelőben a vörösvértestek érését: számuk növelésével megnöveli a vérben raktározott oxigén mennyiségét, és így javítja az oxigénszállítást. A rekombináns EPO az eritropoietin mesterségesen előállított változata, megegyezik a természetes EPO-val az aminosav vázban, csupán a cukorrészekben van csekély eltérés. http://www.sg.hu/cikkek/61527/
http://sportorvos.hu/sportolok/20120409/epo _eritropoietin_a_sportban/ Erythropoietins are used in treating • anemia resulting from chronic kidney disease, • chemotherapy induced anemia in patients with cancer, • inflammatory bowel disease (Crohn's disease and ulcerative colitis) • myelodysplasia from the treatment of cancer (chemotherapy and radiation). Treatments may cause increased risk of death, myocardial infarction, stroke, venous thromboembolism, and tumor recurrence, particularly when used to increase the hemoglobin levels to more than 11 to 12 g/dl.
„Leg”-ek a szénhidrátokkal kapcsolatban Oligonukleotidok, oligopeptidek és oligoszacharidok sokfélesége HO HO HO D-Glc
HO HO
O OH OH
O
HO D-Gal
OH OH
OH HO O HO HO D-Man
HO HO D-Xyl
OH
O
Forrás: P. H. Seeberger et al., ACS Chem. Biol., 2007, 2, 685.
OH OH
3299 emlős oligoszacharid statisztikai elemzése alapján HO HO HO
O
AcNH D-GlcNAc HOOC HO HO D-GlcA HO HO AcNH
HO HO OH
O OH OH
O
HO
OH
AcNH D-GalNAc
O HO HO HOOC OH OH L-IdoA
OH COOH O
OH D-Sia
OH
OH H3C
O
OH
OH HO L-Fuc
Szénhidrátkód
a biológia harmadik nyelve (a nukleinsavak és a fehérjék mellett)
Legbonyolultabb és legváltozatosabb szerkezetek
A cukrok információhordozó kapacitása A képződő izomerek száma sokszorosan felülmúlja bármely más bio(oligo)polimer lehetőségeit Monomer összetétel
Termék
X2
Dimer
1
11
X3
Trimer
1
176
XYZ
Trimer
6
1056
H H2N C COOH R
szekvencia
Izomerek száma Peptidek Szacharidok
HO HO HO
O OH OH
kapcsolódási pont H H2N C COOH R
szekvencia
anomer konfiguráció
HO HO HO
O OH OH
elágazások további módosítások: pl. szulfonil-, foszforil-, acetil-, metilcsoportokkal
Oligonukleotidok, oligopeptidek és oligoszacharidok sokfélesége A szénhidrátkód HO O HO HO OH OH D-Glc (2.5 %; - 0.8 %) HO HO HO
AcNH OH D-GlcNAc (31.8 %; - 8 %)
HO HO AcNH
O OH OH
O
HO OH OH D-Gal (24.8 %; - 23 %) HO HO
O
HOOC HO HO D-GlcA (0.3 %)
HO HO
OH
OH D-Sia (8.3 %; - 26.1 %)
HO HO D-Xyl (0.1 %)
O OH OH
O
HO
AcNH OH D-GalNAc (4.8 %; - 2.3; - 2.2 %) O HO HO HOOC OH OH L-IdoA (0.1 %)
OH COOH O
OH HO O HO HO OH D-Man (18.9 %; - 8.2 %)
OH H3 C
O
OH
OH HO L-Fuc (7.2 %; - 23.8 %)
Forrás: P. H. Seeberger et al., ACS Chem. Biol., 2007, 2, 685.
Monoszacharid Előfordulás (%)
Végcsoportként (%)
3299 emlős oligoszacharid statisztikai elemzése alapján
„Leg”-ek a szénhidrátokkal kapcsolatban Biológiai makromolekulák információtartalma Forrás: J. E. Turnbull, R. A. Field, Nature Chem. Biol., 2007, 3, 74.
Legtöbb információ
a génkészlet nagysága nem képes magyarázni az élővilág sokféleségét és bonyolultságát poszttranszlációs módosulások
Genotípusok – fenotípusok és a glikom Genotípusok A proteom molekuláris és funkcionális diverzitásának növelése a glikom révén A glikom másodlagos géntermékek halmaza, templátja csak a bioszintézist katalizáló enzimeknek van (→ mikroheterogenitás) Az információt hordozó kémiai tér maximális kiterjesztése minimális genetikai ráfordítással
Az emberi génkészlet ~350 glikoziltranszferáz és glikozid hidroláz enzimet kódol (ez a génállomány 1-1.5 %-a).
Forrás: J. E. Turnbull, R. A. Field, Nature Chem. Biol., 2007, 3, 74.
Fenotípusok (a glikozilezésen kívüli más poszttranszlációs módosulásokkal együtt)
A sejtek és környezetük kapcsolata
Szénhidrátok részvétele sejtfelszíni kölcsönhatásokban
Lektinek – szénhidrát felismerő fehérjék (receptorok)
A lektinek és fontosabb biológiai szerepeik Lectins are carbohydrate-binding proteins that are widely conserved in Nature including in animals, plants, and microorganisms. The biological activities of animal lectins include: • receptor-mediated endocytosis of glycoproteins, • cellular recognition and adhesion, • inflammation, • cell growth, • metastasis. The X-ray crystal structures of lectins demonstrate their oligomeric structures and multivalent binding properties. As a consequence, lectin binding to multivalent glycoconjugate receptors on the surface of cells leads to their crosslinking, aggregation and subsequent signal transduction effects.
Multivalencia és következményei a szénhidrát-fehérje kölcsönhatásokban I.
Schematic representations of (A) face-to-face binding of a lectin with three subsites (green) to a trivalent carbohydrate (blue); (B) binding of a nonavalent glycoprotein (orange/black/pink) to two lectin molecules (green); (C) binding of a linear glycoprotein (black/red) to two lectin molecules (green). Adv. Carbohydr. Chem. Biochem., 2010, 63, 139.
Multivalencia a szénhidrát-fehérje kölcsönhatásokban II.
A monoszacharid ligadumok kötődése receptoraikhoz többnyire gyenge (Kass < 106). a) multivalens szénhidrát kötődése oligomer receptorhoz (10-105-szeres erősödés: klaszter effektus) b) receptor-klaszter képződés kiváltása (jelátvitel) c) kapcsolódás elsődleges és másodlagos kötőhelyekhez
d) lokális koncentráció növelése Forrás: L. L Kiessling, J. E. Gestwicki, L. E. Strong, Curr. Opin. Chem. Biol., 2000, 4, 696. J. J. Lundquist, E. J. Toone, Chem. Rev. 2002, 102, 555.
Változatok mesterséges multivalenciára dendrimerek, glikozilezett polipeptidek és más polimerek, liposzómák
Forrás: J. J. Lundquist, E. J. Toone, Chem. Rev. 2002, 102, 555.
A szénhidrátkód harmadik dimenziója - oligoszacharidok konformációja
A szénhidrát kód harmadik dimenziója Differenciális konformer felismerés
A GM1 gangliozid pentaszacharid humán galectin-1-hez (balra) és kolera toxinhoz (jobbra) kötött állapotban Forrás: H.-J. Gabius, H.-C. Siebert, S. André, J. Jiménez-Barbero, H. Rüdiger, ChemBioChem, 2004, 5, 740.
Glikoenzimek – szénhidrátokat átalakító fehérjék
Szénhidrát - enzim kölcsönhatások Szerepük: szénhidrátszármazékok felépítése és lebontása, azaz glikozidos kötések kialakítása és hasítása Glikozil transzferázok
R1 = UDP R2 = cukor
O
C
H O
O 2
O
R1
Glikozid hidrolázok
O O
O
O
H O
C
1
R
O
2
R
H C
O
O
C
O
Az enzimkatalizált reakciók átmeneti állapota glikozíliumion jellegű
O
HOR1
O
2 O R
R
H O
C
O
R1 = alkil, aril, cukor R2 = H
HO
C
O
A glikozid hidrolázok (glikozidázok)
http://www.cazypedia.org/index.php/Glycoside_hydrolases
http://www.cazypedia.org/index.php/Glycoside_hydrolases
http://www.cazypedia.org/index.php/Glycoside_hydrolases
http://www.cazypedia.org/index.php/Glycoside_hydrolases
http://www.cazypedia.org/index.php/Glycoside_hydrolases
A glikozil transzferázok
Two GT inhibitors are currently in clinical use: the glucosylceramide synthase (GCS) inhibitor miglustat (Morbus Gaucher) and the arabinosyltransferase inhibitor ethambutol (tuberculosis).
ChemBioChem 2010, 11, 1939 – 1949
Glikozil donor szubsztrátumok glikozil transzferázok katalizálta átalakításokban
ChemBioChem 2010, 11, 1939 – 1949
Szénhidrátok a gyógyszerkincsben
Míg az élő sejteket alkotó másik három esszenciális vegyületcsoport (nukleinsavak, fehérjék, lipidek) funkcióit, működését ma már relatíve jól ismerjük, a szénhidrátok biológiai szerepének átértékelődése csak az utóbbi néhány évtizedben kezdődött el, és napjainkban is újabb és újabb fiziológiai és patológiai jelenségekről derül ki, hogy a szénhidrátok kulcsszerepet játszanak bennük. A szénhidrátok közvetlenül részt vesznek a legfontosabb betegségek patofiziológiájában, így pl. a halálozási statisztikák élén szereplő szív és keringési betegségekben, a rákban, a diabeteszben, a bakteriális és vírusos fertőzésekben, az Alzheimer-kórban, stb. A szénhidrátok fokozott előtérbe kerülése a biológiai folyamatok megértésében azzal a következménnyel is jár, hogy a jövőben növekvő szerephez jutnak új diagnosztikumok és gyógyszerek kifejlesztésében.
„Klasszikus” szénhidrát-tartalmú gyógyszerek, hatóanyagok
Napjaink gyógyszerkincse ~1800 kémiai entitás ~1500 kismolekula (többségük szintetikus készítmény)
Szénhidrát-tartalmú gyógyszerek száma <100 (~5-6 %) A természetes szénhidrátok farmakodinámiai és farmakokinetikai sajátságai nem felelnek meg a gyógyszerszerűség követelményeinek • vízoldhatóság ↔ oral bioavailability • nem kielégítő stabilitás • gyenge kötődés a biológiai célmolekulához • bonyolult szerkezet és szintézis
A szénhidrátok és konjugátumaik biológiai kölcsönhatásainak jelentős része még felderítetlen
Szénhidráttartalmú gyógyszerek • Monoszacharid származékok (pl. antraciklinek, nukleozidok, nukleotidok, poliének, egyebek) • Diszacharidok és konjugátumaik (pl. Sucralfate, Lactulose, Vankomycin) • Triszacharidok (pl. Tobramycin, Digoxin) • Oligo- és poliszacharidok (pl. heparin és heparinanalóg szacharidok, komplex oligoszacharidok: Streptomycin, Neomycin, Acarbose) • Makrolidok (pl. Erythromycin, Dirithromycin, Clarithromycin, Azithromycin) Forrás: Klyosov, A. A. Carbohydrates and Drug Design in Klyosov, A. A. (ed.), Glycobiology and Drug Design, ACS Symposium Series; American Chemical Society: Washington, DC, 2012.
Szénhidrát vakcinák Patogénekből származó poliszacharidok és immunogén proteinek konjugátumai (konjugált vakcinák) piacon, illetve klinikai kipróbálás alatt vannak baktériumok, gombák, vírusok, paraziták, tumorok ellen. Forrás: R. D. Astronomo and D. R. Burton, Nature Rev. Drug Discov., 2010, 9, 308.
Aminoglikozidok The aminoglycosides form an important group of antibiotic agents and are immediately recognizable as modified carbohydrate molecules. Typically, they have two or three uncommon sugars, mainly aminosugars, attached through glycoside linkages to an aminocyclitol, i.e. an amino-substituted cyclohexane system, which also has carbohydrate origins.
The aminoglycoside antibiotics have a wide spectrum of activity, including activity against some Gram-positive and many Gram-negative bacteria. They are not absorbed from the gut, so for systemic infections they must be administered by injection. However, they can be administered orally to control intestinal flora. The widespread use of aminoglycoside antibiotics is limited by their nephrotoxicity, which results in impaired kidney function, and by their ototoxicity, which is a serious side-effect and can lead to irreversible loss of hearing. They are thus reserved for treatment of serious infections where less toxic antibiotics have proved ineffective. The aminoglycoside antibiotics interfere with protein biosynthesis. Bacterial resistance to the aminoglycoside antibiotics has proved to be a problem, and this has also contributed to their decreasing use.
Aminoglikozidok – Sztreptomicin
Streptomycin is produced by cultures of a strain of Streptomyces griseus, and is mainly active against Gramnegative organisms. Because of its toxic properties it is rarely used in modern medicine except against resistant strains of Mycobacterium tuberculosis in the treatment of tuberculosis.
Aminoglikozidok – Gentamicin
Gentamicin is a mixture of antibiotics obtained from Micromonospora purpurea. Fermentation yields a mixture of gentamicins A, B, and C, from which gentamicin C is separated for medicinal use. This is also a mixture, the main component being gentamicin C1. Gentamicin is clinically the most important of the aminoglycoside antibiotics, and is widely used for the treatment of serious infections, often in combination with a penicillin when the infectious organism is unknown. It has a broad spectrum of activity, but is inactive against anaerobes. It is active against pathogenic enterobacteria such as Enterobacter, Escherichia and Klebsiella, and also against Pseudomonas aeruginosa
Aminoglikozidok – Neomicin
Neomycin has good activity against Gram-positive and Gram-negative bacteria, but is very ototoxic. Its use is thus restricted to oral treatment of intestinal infections (it is poorly absorbed from the digestive tract) and topical applications in eyedrops, eardrops, and ointments.
Glikopeptidek - Bleomicin
Bleomycin is a mixture of glycopeptide antibiotics isolated from cultures of Streptomyces verticillus, and used for its anticancer activity. Bleomycin is a DNA-cleaving drug, causing single and double strand breaks in DNA.
Glikopeptidek - Vankomicin The glycopeptide vancomycin from cultures of Amycolatopsis orientalis (formerly Streptomyces orientalis) is a particularly important antibiotic. It is frequently the last-resort agent in the control of methicillin-resistant Staphylococcus aureus (MRSA), since many strains have become resistant to all other antibiotics. It has activity against Gram-positive bacteria, especially resistant strains of staphylococci, streptococci, and enterococci.
Makrolidok The macrolide antibiotics are macrocyclic lactones with a ring size typically 12–16 atoms, and with extensive branching through methyl substituents. Polyene macrolides are larger in the range 26–38 atoms. The largest natural macrolide structure discovered has a 66-membered ring. Two or more sugar units are attached through glycoside linkages; these sugars tend to be unusual 6-deoxy structures often restricted to this class of compounds. Macrolides are protein synthesis inhibitors.
Eritromicin Erythromycin activity is predominantly against Gram-positive bacteria, and the antibiotic is prescribed for penicillin-allergic patients.
Makrolidok - Avermektinek (spiroketál szerkezeti elemet tartalmaznak)
The avermectins are a group of macrolides with strong anthelmintic, insecticidal, and acaricidal properties, but with low toxicity to animals and humans. Ivermectin is a semi-synthetic 22,23dihydro derivative of avermectin B1a and was first used in veterinary practice against insects, ticks, mites, and roundworms. Although it is a broad spectrum nematocide against roundworms, it is inactive against tapeworms and flatworms, or against bacteria and fungi. It is an extremely potent agent, and is effective at very low dosages. It is now the drug of choice for use against filarial and several other worm parasites in humans, e.g. river blindness caused by the nematode Onchocerca volvulus. The avermectins target the glutamate-gated chloride channels unique to nematodes, insects, ticks, and arachnids, resulting in neuro-muscular paralysis and death.
Polién makrolidok Most polyene macrolides have antifungal properties, but not antibacterial activity. The macrolide ring size ranges from 26 to 38 atoms, and this also accommodates a conjugated polyene of up to seven E double bonds.
Amphotericin is active against most fungi and yeasts, but it is not absorbed from the gut, so oral administration is restricted to the treatment of intestinal candidiasis. It is administered intravenously for treating potentially life-threatening systemic fungal infections. Nystatin is too toxic for intravenous use, but has value for oral treatment of intestinal candidiasis, as lozenges for oral infections, and as creams for topical control of Candida species.
Antraciklinek
A number of anthracycline antibiotics, e.g. doxorubicin (one of the most successful and widely used antitumour drugs) from Streptomyces peuceticus and daunorubicin from Streptomyces coeruleorubicus, have structurally similar tetracyclic skeletons and would appear to be related to the tetracyclines. However, anthraquinone derivatives are intermediates in anthracycline biosynthesis, and the fourth ring is constructed later.
Szívre ható glikozidok
The fundamental pharmacological activity of the cardioactive glycosides resides in the aglycone portion, but is considerably modified by the nature of the sugar at C-3. This increases water solubility and binding to heart muscle. The sugar unit may have one to four monosaccharides.
Szénhidrát-alapú gyógyszerek és tervezésük
Szénhidrátok a gyógyszertervezésben Possible ways to design carbohydrate-based therapeutics: i) Native glycan structures possessing the desired biological activity. This approach suffers from synthetic limitation and metabolic instability of the potential drug. ii) Glycomimetics in which proper modifications allow a stronger interaction with the target receptor; this approach should guarantee a higher in vivo stability and better pharmacokinetic properties. iii) Carbohydrate scaffolds: this approach takes advantage of an unparalleled opportunity to generate libraries of high functional and structural diversity from carbohydrates. iv) Glyco-fused therapeutics: this approach involves the engineering of the drug structure onto a sugar moiety; in this case, the glycidic part of the molecule might address solubility issues (one of the main problems of organic-based drugs) and/or modulate the pharmacokinetic properties.
Expert Opin. Drug Discov. 2010, 5, 721-737.
Természetes glikánok (Native glycan structures)
Heparin and heparan sulfate are naturally occurring linear polysaccharides that are heavily O- and N-sulfated. Heparin from porcine mucosal tissue has been used as an anticoagulant drug for > 80 years.
Another natural oligosaccharide, hyaluronic acid, is extensively used especially in ophthalmology, tissue engineering techniques and against aphtha.
The development of therapeutics based on native glycan structures has been restricted by synthetic limitations. Unlike proteins and nucleic acids, oligosaccharides are difficult to synthesize chemically and there is a lack of general methods for the routine preparation of these compounds, usually requiring multiple selective protection and deprotection steps; hence, the chemical synthesis of oligosaccharides is a major undertaking.
Expert Opin. Drug Discov. 2010, 5, 721-737.
Carbohydrate vaccines Bacterial polysaccharides can induce an adaptive immune response and based on this observation several bacterial carbohydrates have been used for vaccines development against different pathogens. The first example of glycan-based vaccine dates back to 1930, when induction of an antibody response in patients by pneumococcus-specific polysaccharides was observed. Bacterial polysaccharides suffer from being in many cases poor immunogens, as they structurally closely resemble to ‘self’ glycolipids and glycoproteins. The conjugation of the polysaccharide to a carrier protein offers one way of overcoming this problem. Conjugation methods: • reaction of a lysine residue with an activated ester or an isocyanate • reductive amination between lysine and aldehyde groups, suitably introduced in the glycan moiety • condensation of glycan--nucleophiles with glutamate and aspartate residues activated by carbodiimides • the thiol group of cysteine can be used for conjugation of proteins to molecules equipped with an electrophilic group such as maleimide Expert Opin. Drug Discov. 2010, 5, 721-737.
Chemical structures of some tumor-associated carbohydrate antigens (TACAs) I. Cancer cells often display alterations in their glycan repertoire if compared to normal cells, resulting in the accumulation of new structures such as Globo-H, sialyl Lewis x (sLex), Ley, sLea, sTn, TF, GM3, Gb3 and GM2 on the cell surface, usually referred to as tumor-associated carbohydrate antigens (TACAs). Expression of TACAs on glycoproteins and glycolipids is strictly related to the metastatic potential.
Because TACAs are predominantly expressed on cancer tissues, they provide tools both for diagnosis as tumor markers and for therapeutics design.
Expert Opin. Drug Discov. 2010, 5, 721-737.
Chemical structures of some tumor-associated carbohydrate antigens (TACAs) II.
Glikomimetikumok The use of glycomimetics can offer several advantages over their natural counterparts:
• They usually possess increased metabolic and chemical stability • They can be tailor-made with suitable functional groups (pharmacophores) improving the interaction with receptors/enzymes • The chemical synthesis can sometimes be simplified by the introduction of functional groups of choice for chemoselective ligation methods, allowing easy conjugation to other chemical entities, that is, sugar, protein/peptide, solid support, nanoparticle and dendrimers
In some cases, glycomimetics are modified in different positions, rather than the endocyclic or exocylic oxygen, through the introduction of pharmacophoric groups on the sugar backbones; in addition, they can also be designed in order to mimic the enzymatic transition state (TS), which ultimately derives from the parent saccharidic structure. Expert Opin. Drug Discov. 2010, 5, 721-737.
Glikomimetiumok, mint gyógyszerek I.
Carbohydrate and carbohydrate-derived drugs. Structures of currently approved drugs (trade name in brackets). These include glycosidase inhibitors that prevent the digestion of carbohydrates for the treatment of diabetes (voglibose, miglitol and acarbose) and the prevention of influenza virus infections (zanamivir and oseltamivir); and sulphated glycosaminoglycans, which function as anticoagulants by binding to antithrombin III for the treatment of thrombosis (fondaparinux). ). In addition, carbohydrate-derived drugs are used to treat Gaucher’s disease (miglustat), epilepsy (topiramate) Nature Reviews Drug Discovery, 2009, 8, 661.
Glikomimetiumok, mint gyógyszerek II.
Carbohydrate and carbohydrate-derived drugs. Structures of currently approved drugs (trade name in brackets). These include sulphated glycosaminoglycans, which function as anticoagulants by binding to antithrombin III for the treatment of thrombosis (dalteparin, ardeparin, nardoparin and enoxaparin). In addition, carbohydrate-derived drugs are used to treat osteoarthritis (sodium hyaluronate). Nature Reviews Drug Discovery, 2009, 8, 661.
Szénhidrátokon és kölcsönhatásaikon alapuló diagnosztikai és terápiás lehetőségek Diagnosztikumok fejlesztése - I. típusú diabetes – MRI, - glikonanorészecskék cerebrális gyulladásokra – MRI, - daganatos sejtek azonosítása – PET, - metabolic oligosaccharide engineering (MOE) – rákdiagnosztika, - glycan array technológiák infekciók azonosítására
Glikomimetikumok fejlesztése Lektinek (selectin, adhesin, galectin, DC-SIGN, FimH, MAG, stb), mint célpontok gyulladások, tumor metasztázis, bakteriális (TBC, húgyuti) és vírus (HIV, dengue-láz, hepatitis C, ebola, Marburg) fertőzések
Glikoenzimek (glikozid hidrolázok, glikozil transzferázok, glikogén foszforilázok, OGA, OGT, hexózaminidázok, stb), mint célpontok cukorbetegség, szív- és érrendszeri zavarok, neurodegeneratív elváltozások, ízületi gyulladások, hősokk-fehérjék aktiválása
