posted on 2021-05-21, 17:04authored byMarkéta Pimková Polidarová, Petra Břehová, Martin Maxmilian Kaiser, Miroslav Smola, Martin Dračínský, Joshua Smith, Aleš Marek, Milan Dejmek, Michal Šála, Ondrej Gutten, Lubomír Rulíšek, Barbora Novotná, Andrea Brázdová, Zlatko Janeba, Radim Nencka, Evzen Boura, Ondřej Páv, Gabriel Birkuš
Cyclic dinucleotides (CDNs) are second
messengers that bind to
the stimulator of interferon genes (STING) and trigger the expression
of type I interferons and proinflammatory cytokines. Here we evaluate
the activity of 3′,3′-c-di(2′F,2′dAMP)
and its phosphorothioate analogues against five STING allelic forms
in reporter-cell-based assays and rationalize our findings with X-ray
crystallography and quantum mechanics/molecular mechanics calculations.
We show that the presence of fluorine in the 2′ position of
3′,3′-c-di(2′F,2′dAMP) improves its activity
not only against the wild type (WT) but also against REF and Q STING.
Additionally, we describe the synthesis of the acyloxymethyl and isopropyloxycarbonyl
phosphoester prodrugs of CDNs. Masking the negative charges of the
CDNs results in an up to a 1000-fold improvement of the activities
of the prodrugs relative to those of their parent CDNs. Finally, the
uptake and intracellular cleavage of pivaloyloxymethyl prodrugs to
the parent CDN is rapid, reaching a peak intracellular concentration
within 2 h.