Broad spectrum antiviral nucleosides-Our best hope for the future

Abstract

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.

Keywords: Antiviral; Broad-spectrum; Nucleosides; Pandemic; SARS-CoV-2.

Fig. 1

Early modified nucleoside analogues idoxuridine, brivudine, trifluridine, and 6-azauridine.

Fig. 2

Other early modified nucleoside analogues zidovudine, zalcitabine, didanosine, and stavudine.

Fig. 3

Vidarabine and cytarabine, competitive inhibitors of DNA polymerases.

Fig. 4

Approved acyclic nucleosides acyclovir, penciclovir, ganciclovir and their prodrugs valacyclovir, famciclovir, valganciclovir.

Fig. 5

Fleximer analogues of acyclovir, HP-083 and HP-100.

Fig. 6

Phosphonate nucleoside cidofovir and its lipid prodrug brincidofovir.

Fig. 7

Phosphonate nucleoside tenofovir and its two prodrug forms, tenofovir disoproxil fumarate and tenofovir alafenamide.

Fig. 8

General structure of the McGuigan ProTide.

Fig. 9

Mechanism of McGuigan ProTide metabolism.

Fig. 10

Other approved phosphonate nucleosides, adefovir and its prodrug adefovir dipivoxil.

Fig. 11

Nucleoside reverse transcriptase inhibitors entecavir, telbuvidine, emtricitabine, and lamuvidine (L-nucleosides), as well as abacavir and carbovir.

Fig. 12

Two nucleosides that work by lethal mutagenesis ribavirin and taribavirin.

Fig. 13

NHC and its prodrug molnupiravir, another nucleoside that works by lethal mutagenesis.

Fig. 14

Favipiravir.

Fig. 15

Delayed chain terminators, sofosbuvir and uprifosbuvir.

Fig. 16

Delayed chain terminators, GS-441524 and its prodrug Remdesivir.

Fig. 17

Double prodrug AT-527.

Fig. 18

Adenosine analogue islatravir.

Fig. 19

Modified C2’ nucleosides NITD008 and MK-608.

Fig. 20

Galidesivir, one of the immucillin nucleosides.