Annual Reports in Medicinal Chemistry最新文献

The current focus for many researchers has turned to the development of therapeutics that have the potential for serving as broad-spectrum inhibitors that can target numerous viruses, both within a particular family, as well as to span across multiple viral families. This will allow us to build an arsenal of therapeutics that could be used for the next outbreak. In that regard, nucleosides have served as the cornerstone for antiviral therapy for many decades. As detailed herein, many nucleosides have been shown to inhibit multiple viruses due to the conserved nature of many viral enzyme binding sites. Thus, it is somewhat surprising that up until very recently, many researchers focused more on "one bug one drug," rather than trying to target multiple viruses given those similarities. This attitude is now changing due to the realization that we need to be proactive rather than reactive when it comes to combating emerging and reemerging infectious diseases. A brief summary of prominent nucleoside analogues that previously exhibited broad-spectrum activity and are now under renewed interest, as well as new analogues, that are currently under investigation against SARS-CoV-2 and other viruses is discussed herein.

Despite considerable progress in the development of antiviral drugs, among which anti-immunodeficiency virus (HIV) and anti-hepatitis C virus (HCV) medications can be considered real success stories, many viral infections remain without an effective treatment. This not only applies to infectious outbreaks caused by zoonotic viruses that have recently spilled over into humans such as severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), but also ancient viral diseases that have been brought under control by vaccination such as variola (smallpox), poliomyelitis, measles, and rabies. A largely unsolved problem are endemic respiratory infections due to influenza, respiratory syncytial virus (RSV), and rhinoviruses, whose associated morbidity will likely worsen with increasing air pollution. Furthermore, climate changes will expose industrialized countries to a dangerous resurgence of viral hemorrhagic fevers, which might also become global infections. Herein, we summarize the recent progress that has been made in the search for new antivirals against these different threats that the world population will need to confront with increasing frequency in the next decade.

In this minireview we describe our work on the improvement of the nucleobase analogs Favipiravir (T-705) und its non-fluorinated derivative T-1105 as influenza and SARS-CoV-2 active compounds. Both nucleobases were converted into nucleotides and then included in our nucleotide prodrugs technologies cycloSal-monophosphates, DiPPro-nucleoside diphosphates and TriPPPro-nucleoside triphosphates. Particularly the DiPPro-derivatives of T-1105-RDP proved to be very active against influenza viruses. T-1105-derivatives in general were found to be more antivirally active as compared to their T-705 counterpart. This may be due to the low chemical stability of all ribosylated derivatives of T-705. The ribosyltriphosphate derivative of T-1105 was studied for the potential to act as a inhibitor of the SARS-CoV-2 RdRp and was found to be an extremely potent compound causing lethal mutagenesis. The pronucleotide technologies, the chemical synthesis, the biophysical properties and the biological effects of the compounds will be addressed as well.