COVID-19 Pharmacotherapy

Introduction & the biphasic disease model

• COVID-19 — the clinical syndrome caused by SARS-CoV-2, an enveloped, positive-sense single-stranded RNA (+ssRNA) β-coronavirus (same genus as SARS-CoV and MERS-CoV) with a large ~30 kb genome; declared a pandemic after the late-2019 Wuhan outbreak.
• Replication essentials — the genomic +ssRNA acts directly as mRNA, translated into a polyprotein that viral proteases cleave into non-structural proteins including the RNA-dependent RNA polymerase (RdRp, nsp12); the spike (S) glycoprotein binds the ACE2 receptor for entry — the target of neutralising antibodies and vaccines.
• Two therapeutic windows — the governing concept — an early viral-replication phase (first ~5–7 days, mild disease) where antivirals have maximal benefit, and a late host-hyperinflammatory phase (after ~7 days, severe/hypoxaemic disease, the "cytokine storm") where anti-inflammatory immunomodulators, not antivirals, drive the mortality benefit. [WHO] [NIH]
• The right drug at the wrong stage is useless or harmful — the single most important MD-level principle — dexamethasone helps the hypoxaemic patient but worsens survival in the non-oxygen-requiring patient (RECOVERY). [PMID 32678530]
• Selective toxicity — viruses are obligate intracellular parasites, so antivirals must target virus-specific steps — entry/uncoating, the viral polymerase, or virus-specific proteases.