Small-Molecule Galectin Ligands: Structure-Based Optimisation of Affinity and Selectivity

Van Klaveren, Sjors (author), Tomašič, Tihomir (mentor), Nilsson, Ulf J. (comentor)

In the body, all cell surfaces are covered with glycans, and many regulatory components have carbohydrates attached to them, which can aid in their function. Galectins are a family of proteins which can bind to specific glycans and oligosaccharides and cross-link them to influence a wide range of cellular processes. The members of the galectin family are structurally similar and can be involved in the same processes. Inside the cell, galectins have been observed assisting in the detection of exposed glycans on damaged intracellular vesicles, initiating autophagy which helps to clear out damaged cells and bacterial infections. Some galectins have a role in promoting angiogenesis and lymphangiogenesis. This is associated with the repair of damaged tissue and with the growth of tumours. Studies have also implicated galectins in autoimmune disorders and neurodegenerative diseases. The research in this doctoral dissertation focused on the discovery and development of selective, high-affinity ligands for several galectins, with a special focus on galectin-8. Several structurally diverse libraries of compounds were synthesised as part of ligand-based and structure-based approaches. From these libraries, several novel hits for galectin-1, -3, and -8N were discovered and structure–activity relationships identified. These hits were optimised to produce galectin ligands with sub-micromolar affinities and analogues with almost complete selectivity for galectin-8N over all other tested galectins. Such highly selective compounds may help to study the biological roles of galectins and the pathologies in which they are involved. This may also, in turn, lead to galectin-8N inhibitors with a pharmaceutical potential.

• Language: English
• Keywords: Galectins, ligands, inhibitors, drug discovery, molecular dynamics simulations, virtual screening, docking studies, structure-activity relationship, X-ray crystallography.
• Work type: Doctoral dissertation
• Organization: FFA - Faculty of Pharmacy
• Year: 2024
• PID: 20.500.12556/RUL-155554
• Publication date in RUL: 06.04.2024

Secondary language

• Language: Slovenian
• Title: Nizkomolekularni ligandi galektinov: strukturno podprta optimizacija afinitete in selektivnosti

Abstract

V telesu so vse celične površine prekrite z glikani. Tudi na številne regulatorne komponente so vezani ogljikovi hidrati, ki pomagajo pri njihovem delovanju. Galektini so družina proteinov, ki se vežejo na določene glikane in oligosaharide ter jih navzkrižno povežejo, s čimer vplivajo na širok spekter celičnih procesov. Člani družine galektinov so strukturno podobni in so lahko vključeni v iste ali različne procese. V notranjosti celice so prisotni galektini, ki pomagajo pri odkrivanju izpostavljenih glikanov na poškodovanih znotrajceličnih veziklih, kar sproži avtofagijo, ki pomaga odstraniti poškodovane celice in bakterijske okužbe. Nekateri galektini imajo vlogo pri spodbujanju angiogeneze in limfangiogeneze, kar je povezano z obnovo poškodovanega tkiva in rastjo tumorjev. Študije so pokazale tudi vpletenost galektinov v avtoimunske in nevrodegenerativne bolezni. Raziskave v tej doktorski disertaciji so bile osredotočene na odkrivanje in razvoj selektivnih ligandov z visoko afiniteto za več galektinov, s posebnim poudarkom na galektinu-8. Sintetizirali smo več strukturno raznolikih knjižnic spojin, ki smo jih načrtovali na podlagi struktur znanih ligandov in struktur proteinov. Odkrili smo več novih zaviralcev galektinov-1, -3 in -8N ter postavili razmerja med strukturo in delovanjem. Izhodiščne spojine smo optimizirali do spojin s submikromolarnimi afinitetami in analogov s skoraj popolno selektivnostjo za galektin-8N glede na ostale testirane galektine. Takšne visoko selektivne spojine so uporabne za preučevanje biološke vloge galektina-8 in patologij, v katere je vključen. To lahko posledično vodi tudi do zaviralcev galektina-8N s farmacevtskim potencialom.

• Keywords: Galektini, ligandi, inhibitorji, odkrivanje zdravil, simulacije molekularne dinamike, virtualno presejanje, študije priklopa, razmerje struktura-aktivnost, rentgenska kristalografija.