Opportunities and Challenges in Targeting the Proofreading Activity of SARS-CoV-2 Polymerase Complex

Area of Science:

• Virology
• Molecular Biology
• Drug Discovery

Background:

• Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes the COVID-19 pandemic.
• Existing vaccines and antivirals show promise, but alternative strategies are needed.
• Coronaviruses possess a unique RNA proofreading mechanism for genome replication.

Purpose of the Study:

• To review the role of non-structural protein 14 (NSP14) and its exonuclease (ExoN) activity in SARS-CoV-2 replication.
• To describe assays for assessing NSP14 ExoN function.
• To review inhibitors targeting NSP14 proofreading activity.

Main Methods:

• Literature review of SARS-CoV-2 replication mechanisms.
• Analysis of assays developed for ExoN function assessment.
• Compilation of known nucleoside and non-nucleoside inhibitors.

Main Results:

• NSP14's ExoN activity is crucial for SARS-CoV-2 genome fidelity.
• Various assays have been established to measure ExoN proofreading.
• Nucleoside analogs and non-nucleoside inhibitors targeting ExoN are documented.

Conclusions:

• Inhibiting NSP14's proofreading function is a potential therapeutic strategy for COVID-19.
• Combination therapy with non-nucleoside inhibitors and chain-terminating nucleosides is a promising research direction.
• Further validation is needed for non-nucleoside proofreading inhibitors as anti-coronavirus agents.