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Review
. 2022 Mar 17;25(4):104112.
doi: 10.1016/j.isci.2022.104112. eCollection 2022 Apr 15.

Mono- and combinational drug therapies for global viral pandemic preparedness

Aleksandr Ianevski  1 , Rouan Yao  1 , Ronja M Simonsen  1 , Vegard Myhre  1 , Erlend Ravlo  1 , Gerda D Kaynova  2 , Eva Zusinaite  3 , Judith M White  4 , Stephen J Polyak  5 , Valentyn Oksenych  1 , Marc P Windisch  6 , Qiuwei Pan  7 , Eglė Lastauskienė  8 , Astra Vitkauskienė  9 , Algimantas Matukevičius  9 , Tanel Tenson  3 , Magnar Bjørås  1 , Denis E Kainov  1   3   10
Affiliations
Review

Mono- and combinational drug therapies for global viral pandemic preparedness

Aleksandr Ianevski et al. iScience. .

Abstract

Broadly effective antiviral therapies must be developed to be ready for clinical trials, which should begin soon after the emergence of new life-threatening viruses. Here, we pave the way towards this goal by reviewing conserved druggable virus-host interactions, mechanisms of action, immunomodulatory properties of available broad-spectrum antivirals (BSAs), routes of BSA delivery, and interactions of BSAs with other antivirals. Based on the review, we concluded that the range of indications of BSAs can be expanded, and new pan- and cross-viral mono- and combinational therapies can be developed. We have also developed a new scoring algorithm that can help identify the most promising few of the thousands of potential BSAs and BSA-containing drug cocktails (BCCs) to prioritize their development during the critical period between the identification of a new virus and the development of virus-specific vaccines, drugs, and therapeutic antibodies.

Keywords: Chemistry; Pharmaceutical preparation; Pharmaceutical science; Pharmacology.

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Conflict of interest statement

The authors declare no competing interests.

Figures

None
Graphical abstract
Figure 1
Figure 1
Drug activity-virus phylogeny relationship analysis (A) Phylogenetic tree of viruses constructed based on the amino acid sequences of viral pols and RTs. (B) Bar chart showing the number of BSAs active against the viruses shown in panel (A). (C) Venn diagrams showing the number of BSAs targeting closely related viruses.
Figure 2
Figure 2
Structure-activity relationship analysis identifies compounds structurally similar to known BSAs The circular dendrogram shows the SAR of BSAs from our database. We also used SAR analysis to identify BSA candidates from the list of 11,834 compounds from DrugBank. Three compound sub-clusters that include two or more know BSAs are shown.
Figure 3
Figure 3
Virus and host targets for BSAs (A) Eye diagram showing virus-directed BSAs linked to viruses through potential targets. (B) Eye diagram showing host-directed BSAs linked to viruses through potential targets. (C) Common targets of 58 BSAs, which possess immunomodulatory properties. Targets with interaction group scores <0.05 as well as unique targets were omitted. Clustering was performed to show highlight targets for BSAs.
Figure 4
Figure 4
Drug-target interactions in BSA-containing combinations (A) Developmental statuses and targets of BCCs. (B) Examples of BCCs targeting virus, host, or both factors. A random walks algorithm was used to group the drug combinations based on their targets (Wang et al., 2020).
Figure 5
Figure 5
Routes of administration (RoA) of BSAs and BCCs (A) Organ systems that are preferentially affected by different viruses. (B) RoA of BSAs. Sizes of the colored bubbles reflect the number of BSAs developed against a certain virus. (C) RoA of BCCs. Colored squares indicate the combined RoA of drugs in BCCs. Gray shading indicates that antiviral activity has either not been studied or reported for the drug combination in question. Data S1. Broad-spectrum antivirals (BSAs), their targets, mechanisms of action, immunomodulatory properties, routes of delivery, BSA-containing drug combinations (BCCs), and BSA and BCC scores.
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