Pregled raziskav ligandov za sialično kislino vežoča lektina imunoglobulinskega tipa 7 in 8

Gicheva, Sofija (avtor), Mravljak, Janez (mentor)

Ozadje: Sialične kisline se nahajajo na koncu sladkornih verig glikoproteinov in celičnih komponent, ki gradijo glikokaliks. Ta obdaja celične membrane in je udeležen v številnih medceličnih interakcijah. Sialične kisline so prav tako udeležene v številnih fizioloških in patofizioloških procesih. Potrjeno je, da so udeležene pri okužbah z različnimi patogeni, pri motnjah delovanja imunskega sistema in rakavih obolenjih. Tvorijo interakcije z lektini, in sicer s selektini, faktorjem H in lektini imunoglobulinskega tipa, ki vežejo sialične kisline (Siglec). Namen dela: Siglec-7 in Siglec-8 sta najmanj proučena receptorja iz družine Siglec receptorjev. Izhajajoč iz tega vidika je namen magistrske naloge pregled obstoječih raziskav, ki opisujejo interakcije Siglec-7 ter Siglec-8 z glikomimetiki sialičnih kislin. Obravnavali smo majhne molekule, ki imajo učinkovinam podobne lastnosti in so zasnovane na sialičnih kislinah. Osredotočili smo se na interakcije, ki jih tvorijo s tarčo, z vidika selektivnosti in afinitete vezave. Metode: Pri izboru raziskav smo sledili smernicam »Priporočene postavke poročanja za sistematični pregled in metaanalizne protokole« (PRISMA). Določili smo iskalni niz, na podlagi katerega smo dobili raziskave, ki so vsebovale podatke o ligandih Siglec-7 oziroma Siglec 8, njihovi strukturi in afiniteti vezave. Vključili smo tudi nekaj raziskav, ki opisujejo mehanizem razvoja patofizioloških sprememb in vpliv sialičnih kislin ob tem, in pa raziskave, ki opisujejo receptorje Siglec. Rezultati: Upoštevajoč smernice PRISMA smo iz PubMed in Web of Science izbrali 21 člankov, ki smo jih obravnavali. Naredili smo analizo raziskav po državi in letu objave. Nato smo opisali značilnosti vsake raziskave in podrobneje opisali tiste, ki najbolj ustrezajo namenom magistrske naloge. Podrobneje smo opisali še strukturo glikomimetikov, ki se najmočneje vežejo z receptorjema, predstavljenima z vrednostjo konstante disociacije ali IC50. Sklep: Raziskave so potrdile, da je afiniteta vezave receptorja z naravnimi sladkorji bistveno nižja v primerjavi z afiniteto vezave, ustvarjeno z glikomimetiki. Dodatno receptorji Siglec zaznajo razliko med konformacijo in tipom glikozidnih vezi, ki se tvorijo med posameznimi sladkornimi enotami, kar je dokaz o selektivnosti receptorjev v tej skupini.

• Jezik: Slovenski jezik
• Ključne besede: receptorji Siglec, sialične kisline, glikomimetiki
• Vrsta gradiva: Magistrsko delo/naloga
• Organizacija: FFA - Fakulteta za farmacijo
• Leto izida: 2021
• PID: 20.500.12556/RUL-132217
• Datum objave v RUL: 17.10.2021

Sekundarni jezik

• Jezik: Angleški jezik
• Naslov: Research review on ligands of sialic acid-binding immunoglobulin-type lectins 7 and 8

Izvleček

Background: Sialic acids are located at the termini of glycoproteins and glycans, which build the glycocalyx. As such, they are involved in numerous cell-cell interactions. This includes physiological and pathological processes. They interact with lectins, specifically with selectins, factor H, and sialic acid binding immunoglobulin like lectins – Siglecs. Siglecs are emerging as potential therapeutic targets, for treatment of immune cell disorders and cancer. Aim: Siglec-7 and Siglec-8 are receptors from the Siglec family, and least researched ones. They are expressed on immune cells and play a role in disorders of the immune system. From this point of view, our aim was to conduct a review of research articles, whose main focus are the interactions between Siglec-7 or Siglec-8 with glycomimetics – analogues of sialic acids. In the review, we included small molecules, whose structure is based on the structure of native sialic acids and have drug like properties. Our focus were the selectivity and affinity of binding of these analogues with Siglec-7 and Siglec-8. Methods: We conducted the search using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We defined the search profile, on the basis of which we conducted the search in PubMed and Web of Science. We included the research articles that mentioned small molecules, that bind to Siglec-7 and Siglec-8, preferentially with a defined Kd or IC50. We included articles, which explain in detail the functions of sialic acids in cancer as well as immune disorders, and articles that examine the structure of Siglec receptors. Results: According to the PRISMA guidelines, we extracted 21 research articles from PubMed and Web of Science and included them in the review. We categorised the articles according to the country, where the research took place. Another analysis was according to the year of publication of the same articles. Conclusion: The review showed that the binding affinity of the receptors with native glycans is significantly lower than the binding affinity with glycomimetics. Siglec receptors distinguish a difference between the types of bonds formed between the monosaccharides and show different preferences for different bonding conformations.

• Ključne besede: Siglec receptors, sialic acids, glycomimetics