Autor: Gilbert, Sandra M. - Prolib Integro

Skocz do pozycji: 1.

Tytuł:: The madwoman in the attic : the woman writer and the nineteenth century imagination
Bliźniacza siostra grozy : potworna Ewa Marii Shelley
Autorzy:: Gilbert, Sandra M.
Gubar, Susan
Współwytwórcy:: Bilczewski, Tomasz
Kowalcze-Pawlik, Anna
Wydawca:: Towarzystwo Autorów i Wydawców Prac Naukowych Universitas
Dostawca treści:: Repozytorium Uniwersytetu Jagiellońskiego

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Skocz do pozycji: 2.

Tytuł:: Crystallographic characterisation and development of bi-substrate inhibitors of coronavirus nsp14 methyltransferase
Autorzy:: Ahmad, Shamshad A.
Scott, Duncan E.
Saikatendu, Kumar Singh
See, Kexin
Urakova, Nadya
Wanningen, Patrick
Kresik, Leanid
Snijder, Eric J.
O'Neill, Sandra
Czarna, Anna
Gilbert, Ian H.
Grygier, Przemysław
Delpal, Adrien
Post, John M.
Eadsforth, Thomas
Norval, Suzanne
O'Byrne, Sean N.
Pyrć, Krzysztof
Wierzbicka, Kinga
Smith, Craig D.
Decroly, Etienne
Matsuda, Alex
Georgiou, Irene
Groenewold, Mirjam
Chang, Edcon
Plewka, Jacek
Robinson, Colin
Opis:: SARS-CoV-2 non-structural protein 14 (nsp14) is essential for viral mRNA cap guanine-N7 methylation and represents a promising but underexplored antiviral target. Herein we describe a structure-guided campaign based on a hit from a focussed SAM mimetic library. Systematic SAR exploration guided by six X-ray co-crystal structures in complex with SARS-CoV-2 led to compound 26, a bi-substrate inhibitor that bridges the SAM and RNA cap binding sites. Compound 26 achieved nanomolar potency against nsp14 from SARS-CoV-2 ($IC_{50}$ = 53 nM), SARS-CoV-1, and two alphacoronaviruses, with excellent selectivity over human RNMT and flaviviral MTase. In general, the compounds demonstrated favourable metabolic stability, passive permeability, and no HepG2 cytotoxicity. However, cellular antiviral activity was limited, revealing disconnects between enzyme inhibition and phenotypic response. These findings provide a structural framework for optimizing bi-substrate methyltransferase inhibitors against coronaviruses with a view for pan-coronaviral activity.
Dostawca treści:: Repozytorium Uniwersytetu Jagiellońskiego

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