Repozytorium
Wyszukaj
Kolekcje
Inne
Structure-based design, synthesis, and evaluation of the biological activity of novel phosphoroorganic small molecule IAP antagonists.
Autorzy
Rok wydania
2020
Czasopismo
Numer woluminu
38
Strony
1350-1364
DOI
10.1007/s10637-020-00923-4
Kolekcja
Język
Angielski
Typ publikacji
Artykuł
One of the strategies employed by novel anticancer therapies is to put the process of apoptosis back on track by blocking the interaction between inhibitor of apoptosis proteins (IAPs) and caspases. The activity of caspases is modulated by the caspases themselves in a caspase/procaspase proteolytic cascade and by their interaction with IAPs. Caspases can be released from the inhibitory influence of IAPs by proapoptotic proteins such as secondary mitochondrial activator of caspases (Smac) that share an IAP binding motif (IBM). The main purpose of the present study was the design and synthesis of phosphorus-based peptidyl antagonists of IAPs that mimic the endogenous Smac protein, which blocks the interaction between IAPs and caspases. Based on the structure of the IAP antagonist and recently reported thiadiazole derivatives, we designed and evaluated the biochemical properties of a series of phosphonic peptides bearing the N-Me-Ala-Val/Chg-Pro-OH motif (Chg: cyclohexylglycine). The ability of the obtained compounds to interact with the binding groove of the X-linked inhibitor of apoptosis protein baculovirus inhibitor of apoptosis protein repeat (XIAP BIR3) domain was examined by a fluorescence polarization assay, while their potential to induce autoubiquitination followed by proteasomal degradation of cellular IAP1 was examined using the MDA-MB-231 breast cancer cell line. The highest potency against BIR3 was observed among peptides containing C-terminal phosphonic phenylalanine analogs, which displayed nanomolar Ki values. Their antiproliferative potential as well as their proapoptotic action, manifested by an increase in caspase-3 activity, was examined using various cell lines.
Słowa kluczowe
IAP antagonist, smac mimetic, apoptosis, phosphoroorganic
Licencja otwartego dostępu
Licencja na prawach której można swobodnie kopiować, rozprowadzać, zmieniać i remiksować objęty prawem autorskim utwór (Utwór-przedmiot prawa autorskiego) pod warunkiem podania imienia i nazwiska autora utworu pierwotnego oraz źródła pochodzenia utworu.
Pełny tekst licencji: https://creativecommons.org/licenses/by/3.0/pl/legalcode
Adres publiczny
http://dx.doi.org/10.1007/s10637-020-00923-4
Strona internetowa wydawcy
Podobne publikacje
The pro-apoptotic action of new analogs of the insect gonadoinhibiting peptide Neb-colloostatin: synthesis and structure-activity studies.
Kuczer Mariola, Czarniewska Elżbieta, Rosiński Grzegorz, Lisowski Marek
The pro-apoptotic action of the peptide hormone Neb--colloostatin on insect haemocytes.
Czarniewska Elżbieta, Mrówczyńska L., Kuczer Mariola, Rosiński Grzegorz
CuI and CuII complexes with phosphine derivatives of fluoroquinolone antibiotics : a comparative study on the cytotoxic mode of action.
Bykowska Aleksandra, Komarnicka Urszula K., Jeżowska-Bojczuk Małgorzata, Kyzioł Agnieszka
