SEARCH RESULTS FOR: pharmaceuticals-under-investigation-by-who-for-treating-covid-19-proposed-mechanisms

pharmaceuticals-under-investigation-by-who-for-treating-covid-19-proposed-mechanisms

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