J Med Chem. 2018 Jun 15. doi: 10.1021/acs.jmedchem.8b00617. [Epub ahead of print]
Prodrugs of the Phosphoribosylated Forms of Hydroxypyrazinecarboxamide Pseudobase T-705 and its De-Fluoro-Analogue T-1105 as Potent Influenza Virus Inhibitors.
Huchting J, Vanderlinden E, Winkler M, Nasser H, Naesens L, Meier C.
Abstract
We here disclose chemical synthesis of ribonucleoside 5'-mono- (RMP), -di- (RDP), and -triphosphate (RTP), and cycloSal-, DiPPro-, and TriPPPro-nucleotide-prodrugs of the antiviral pseudobase T-1105. Moreover, we include one nucleoside-diphosphate-prodrug of the chemically less stable T-705. We demonstrate efficient T-1105-RDP- and -RTP-release from the DiPPro- and TriPPPro-compounds by esterase activation. Using crude enzyme extracts, we saw rapid phosphorylation of T-1105-RDP into T-1105-RTP. In sharp contrast, phosphorylation of T-1105-RMP was not seen, indicating a yet unrecognized bottleneck in T-1105's metabolic activation. Accordingly, DiPPro- and TriPPPro-compounds displayed improved cell culture activity against influenza A and B virus, which they retained in a mutant cell line incapable of activating the nucleobase parent. T-1105-RTP had a strong inhibitory effect against isolated influenza polymerase and DiPPro-T-1105-RDP showed four-fold higher potency in suppressing one-cycle viral RNA synthesis versus T-1105. Hence, our T-1105-RDP- and -RTP-prodrugs improve antiviral potency and achieve efficient metabolic bypass.
PMID: 29906392 DOI: 10.1021/acs.jmedchem.8b00617
Prodrugs of the Phosphoribosylated Forms of Hydroxypyrazinecarboxamide Pseudobase T-705 and its De-Fluoro-Analogue T-1105 as Potent Influenza Virus Inhibitors.
Huchting J, Vanderlinden E, Winkler M, Nasser H, Naesens L, Meier C.
Abstract
We here disclose chemical synthesis of ribonucleoside 5'-mono- (RMP), -di- (RDP), and -triphosphate (RTP), and cycloSal-, DiPPro-, and TriPPPro-nucleotide-prodrugs of the antiviral pseudobase T-1105. Moreover, we include one nucleoside-diphosphate-prodrug of the chemically less stable T-705. We demonstrate efficient T-1105-RDP- and -RTP-release from the DiPPro- and TriPPPro-compounds by esterase activation. Using crude enzyme extracts, we saw rapid phosphorylation of T-1105-RDP into T-1105-RTP. In sharp contrast, phosphorylation of T-1105-RMP was not seen, indicating a yet unrecognized bottleneck in T-1105's metabolic activation. Accordingly, DiPPro- and TriPPPro-compounds displayed improved cell culture activity against influenza A and B virus, which they retained in a mutant cell line incapable of activating the nucleobase parent. T-1105-RTP had a strong inhibitory effect against isolated influenza polymerase and DiPPro-T-1105-RDP showed four-fold higher potency in suppressing one-cycle viral RNA synthesis versus T-1105. Hence, our T-1105-RDP- and -RTP-prodrugs improve antiviral potency and achieve efficient metabolic bypass.
PMID: 29906392 DOI: 10.1021/acs.jmedchem.8b00617