Nucleotide Analogues as Inhibitors of Viral Polymerases

Jingyue Ju; Shiv Kumar; Xiaoxu Li; Steffen Jockusch; James J. Russo

Examples of nucleotide analogues designed by us to satisfy these criteria are provided in Fig. 6 , and strategies for their synthesis in Figs. 7-9; Fig. 10 shows the activation of these prodrugs to form triphosphate analogues (same as for sofosbuvir in Fig. 3 ) that should be incorporated and inhibit the coronavirus and other RNA virus polymerases. The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/2020.01.30.927574 doi: bioRxiv preprint The copyright holder for this preprint (which was not peer-reviewed) is the . https: //doi.org/10.1101 //doi.org/10. /2020 Synthesis of 3'-O-blocked nucleoside phosphoramidate prodrugs can be carried out starting from 2'-modified nucleosides (Ross et al 2011) . First, both the 5'-OH and the exocyclic amino group of the base will be protected. Then the 3'-OH will be derivatized with a variety of blocking groups, including methyl, ethyl, propyl, allyl, propargyl, methoxymethyl, methylthiomethyl, azidomethyl, etc ., such as those listed in Fig.6 , following established methods (Ju et al 2006 , Guo et al 2008 . After deprotection, the free 5'-OH is derivatized to afford the corresponding phosphoramidates by treatment with freshly prepared chlorophosphoramidate reagent in the presence of N-methyl imidazole (Sofia et al 2010) . Fig. 7 and Fig. 8 show example synthetic routes for the 3'-methoxy and 3'-O-methylthiomethyl nucleoside phosphoramidate analogs, respectively. Alternatively, starting from a 2'-modified nucleoside, the 5'-OH can be derivatized first to give 5'-phosphoramidate nucleotides, followed by 3'-OH derivatization to afford 3'-O blocked nucleoside phosphoramidate analogues. Fig. 9 shows an example synthetic route for 3'-allyl nucleoside phosphoramidate analogues.