A rational roadmap for SARS-CoV-2/COVID-19 pharmacotherapeutic research and development: IUPHAR Review 29

Abstract

In this review, we identify opportunities for drug discovery in the treatment of COVID-19 and, in so doing, provide a rational roadmap whereby pharmacology and pharmacologists can mitigate against the global pandemic. We assess the scope for targeting key host and viral targets in the mid-term, by first screening these targets against drugs already licensed, an agenda for drug repurposing, which should allow rapid translation to clinical trials. A simultaneous, multi-pronged approach using conventional drug discovery methods aimed at discovering novel chemical and biological means of targeting a short list of host and viral entities which should extend the arsenal of anti-SARS-CoV-2 agents. This longer term strategy would provide a deeper pool of drug choices for future-proofing against acquired drug resistance. Second, there will be further viral threats, which will inevitably evade existing vaccines. This will require a coherent therapeutic strategy which pharmacology and pharmacologists are best placed to provide. LINKED ARTICLES: This article is part of a themed issue on The Pharmacology of COVID-19. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.21/issuetoc.

FIGURE 1

The SARS‐CoV‐2 life cycle. The novel virus uses ACE2 to attach to target cells, including epithelial and endothelial cells, particularly in the lungs. SARS‐CoV‐2 requires the camostat‐sensitive serine proteinase TMPRSS2 to prime the spike protein for fusion and internalization. Thereafter, host cellular processes are exploited for viral replication and release from the cell. ACE2 is also expressed in high levels in the GI tract, where it is associated with B⁰AT1/SLC6A19 that actively transports neutral amino acids across the apical membrane of epithelial cells. The serine proteinase ADAM17, present on cell surfaces, cleaves ACE2 to release an ectodomain of ACE2, including the active site, into the circulation. This circulating form of ACE2 may also bind SARS‐CoV‐2, but this complex is predicted not to internalize and therefore could be exploited as a beneficial viral decoy. Recombinant ACE2 (GSK2586881) has been tested in Phase 2 clinical trials for the potential treatment of acute respiratory distress syndrome, but it is not yet established if the compound will reduce viral load by acting as a decoy

FIGURE 2

A cartoon of the virus structure, identifying the four structural proteins and the viral genome