Accelerating antiviral drug discovery: lessons from COVID-19

Abstract

During the coronavirus disease 2019 (COVID-19) pandemic, a wave of rapid and collaborative drug discovery efforts took place in academia and industry, culminating in several therapeutics being discovered, approved and deployed in a 2-year time frame. This article summarizes the collective experience of several pharmaceutical companies and academic collaborations that were active in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antiviral discovery. We outline our opinions and experiences on key stages in the small-molecule drug discovery process: target selection, medicinal chemistry, antiviral assays, animal efficacy and attempts to pre-empt resistance. We propose strategies that could accelerate future efforts and argue that a key bottleneck is the lack of quality chemical probes around understudied viral targets, which would serve as a starting point for drug discovery. Considering the small size of the viral proteome, comprehensively building an arsenal of probes for proteins in viruses of pandemic concern is a worthwhile and tractable challenge for the community.

Synthesis and Evaluation of 9-Aminoacridines with SARS-CoV-2 Antiviral Activity

“…While there has been considerable progress made on COVID-19 drug discovery in over 3 years since the pandemic began with preclinical and clinical molecules showing activity, , there is still a need to identify promising lead compounds . This may be particularly important as they may be needed as the virus mutates and overcomes existing small-molecule antivirals.…”

“…As of September 20, 2023, the COVID-19 pandemic has ended based on the WHO recommendation. However, there are very few small molecule treatments developed for this disease , and preparation for future outbreaks of this virus or related viruses is still of great importance . COVID-19 is an infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).…”

A community effort in SARS‐CoV‐2 drug discovery

“…The RNA genome of SARS-CoV-2 encodes 29 structural, non-structural (Nsp) and accessory proteins, which are responsible for entry and uncoating, replication, and assembly [26]. The large, multidomain transmembrane papain-like protease (Nsp3 or PLpro), the main protease (Nsp5, 3CLpro or Mpro), the RNA-dependent RNA Polymerase (RdRP or Nsp12), the nucleocapsid (N), the spike protein (S), and the human host transmembrane protease (TMPRSS2), are frequently named as potential drug targets [27][28][29][30][31][32][33][34]. Due to the frequent mutations in the spike protein S, other proteins are deemed more suitable as drug targets.…”

Discovery of High Affinity Cyclic Peptide Ligands for Human ACE2 with SARS-CoV-2 Entry Inhibitory Activity

“…It is therefore imperative that prophylactic vaccine administration be supplemented with effective drug regimens to reduce symptom severity and shorten the period of infectiousness, particularly in groups at high risk of serious illness. 11,12 With COVID-19 transmission seemingly endemic for the foreseeable future, there has been significant research effort to develop effective therapeutics for this disease. Antivirals represent an important class of therapeutics, particularly during early treatment of symptomatic patients for the prevention of disease progression shortly after infection.…”

“…With continued global spread in significant numbers, immunocompromised individuals and the elderly are at continued risk with high disease severity and death. It is therefore imperative that prophylactic vaccine administration be supplemented with effective drug regimens to reduce symptom severity and shorten the period of infectiousness, particularly in groups at high risk of serious illness. , …”