Pharmaceuticals under investigation by WHO for treating
Author: Hannah Yaphe Reviewers: Davis Maclean, Timothy Fu,
COVID-19 (Corona Virus Disease 2019):
Yan Yu*, Stephen Vaughan*
* MD at time of publication
Note: This slide is based on literature available up to 03/30/2020. Medicines shown here are those included in the WHO SOLIDARITY trial, which were selected based on in vitro work and clinical data from MERS and SARS. Mechanisms are preliminary and there is insufficient data to support or refute the use of these agents for COVID- 19. Research is ongoing.
Viral replication is terminated
Fewer new cells infected
↓ activation of inflammatory and immune responses
Improvement or halt in progression of clinical signs of infection*
*See slide on pathophysiology and clinical findings of COVID19
Proposed Mechanisms
COVID-19 Viral Replication Pathway
Virus adheres to Angiotensin Converting Enzyme 2 (ACE-2) receptor on body cells
Endocytosis of virus in clathrin coated vesicles
Vesicles mature through endolysosomal pathway
Virus membrane fuses with mature endolysosome releasing viral RNA into cytosol
Viral RNA uses host cell ribosomes to make new viral proteins like RNA-polymerase
Viral RNA-polymerase incorporates nucleotides from the host cell
New viral RNA is produced
Viral RNA and proteins packaged into new viral particles
Viral particles released from cell
Chloroquine or Hydroxychloroquine (CQ, HCQ)
Weak basicity leads to ↑ pH of endosomes and lysosomes
N-terminal glycosylation of ACE-2 in Golgi is inhibited
Abnormal ACE-2 receptor expressed on cell surface
Viral membrane cannot fuse with immature endosome
Altered virus- ACE-2 interaction impairs entry into host cell
Viral contents are not released
Interferon-β (IFNβ) (Given with LPV/RTV)
Ritonavir (RTV)
(given with LPV)
Inhibition of CYP450, a drug metabolizing enzyme
↓ degradation of Lopinavir (LPV)
↑ plasma half life and duration of action of LPV
Binding to interferon receptor
Impaired maturation of endosomes
Activation of JAK/STAT pathway
Transcription of IFN- regulated genes
↑ expression of antiviral and immunomodulatory proteins
Antiviral effects may ↑ response to LPV/RTV (mechanism uncertain)
Remdesivir (RDV)
RDV is phosphorylated to RDV-triphosphate (RDV-TP)
Lopinavir (LPV)
Inhibition of viral 3- chymotripsin-like protease
Inhibition of viral replication (multiple mechanisms)
RDV-TP competes with ATP for binding to viral RNA polymerase
Viral protein precursors are not cleaved into mature viral proteins
Incorporation of RDV-TP terminates growing RNA
Newly formed viral particles can’t infect new cells
Legend:
Pathophysiology
Mechanism
Sign/Symptom/Lab Finding
Complications
Published March 30, 2020 on www.thecalgaryguide.com