Discovery and development of safe-in-man broad-spectrum antiviral agents

Abstract

Viral diseases are one of the leading causes of morbidity and mortality in the world. Virus-specific vaccines and antiviral drugs are the most powerful tools to combat viral diseases. However, broad-spectrum antiviral agents (BSAAs, i.e. compounds targeting viruses belonging to two or more viral families) could provide additional protection of the general population from emerging and re-emerging viral diseases, reinforcing the arsenal of available antiviral options. Here, we review discovery and development of BSAAs and summarize the information on 120 safe-in-man agents in a freely accessible database (https://drugvirus.info/). Future and ongoing pre-clinical and clinical studies will increase the number of BSAAs, expand the spectrum of their indications, and identify drug combinations for treatment of emerging and re-emerging viral infections as well as co-infections.

Keywords: Antiviral drug; BSAAs; Broad-spectrum antiviral agents; Drug discovery and development; Virus.

Figure 1

Discovery of novel activities and follow-up development of broad-spectrum antiviral agents (BSAAs). Yellow shading indicates a process of discovery and development of safe-in-man BSAAs, for which pharmacokinetic (PK) properties in pre-clinical (animal model) and early clinical developmental phases (phase 0-IIa trials) are already available. Abbreviations: ESCs, human embryonic stem cells; iPSCs, human induced pluripotent stem cells (iPSCs).

Figure 2

ABC of BSAA development process. (A) Testing BSAA toxicity (left panel) and efficacy (right panel) in immortalized cell cultures and co-cultures. (B) Testing BSAA toxicity (left panel) and efficacy (right panel) in animal models. If BSAA is repositioned from another disease (i.e. its PK/PD and toxicity profiles are available for the animal model) it could bypass the safety studies. (C) Clinical trials of BSAAs. (Left panel) Pharmacokinetics (PK) and safety studies. (Right panel) Efficacy studies. If the drug is repositioned from another disease (i.e. its safety profile in man is available) it could bypass the PK and safety studies in man.

Figure 3

Safe-in-man broad-spectrum antiviral agents (BSAAs) and viruses they inhibit. A snapshot is taken from https://drugvirus.info/ website. Viruses are clustered by virus groups. BSAAs range from the highest to lowest number of targeted viruses. Different shadings indicate different development status of BSAAs. Gray shading indicates that the antiviral activity has not been either studied or reported. Abbreviations: ds, double-stranded; RT, reverse transcriptase; ss, single-stranded.

Figure 4

Structure-activity relationship of safe-in-man BSAAs. Web-application serves C-SPADE was used to cluster BSAAs based on their structural similarities and visualize them as a dendrogram of compounds augmented with their functional annotations (https://cspade.fimm.fi/).

Figure 5

Safe-in-man broad-spectrum antiviral agents and coronaviruses they inhibit. A snapshot is taken from https://drugvirus.info/ website. Different shadings indicate different development status of BSAAs. Grey shading indicates that the antiviral activity has not been either studied or reported.