Inhibition of SARS-CoV-2 entry through the ACE2/TMPRSS2 pathway: a promising approach for uncovering early COVID-19 drug therapies
Top Cited Papers
- 21 July 2020
- journal article
- review article
- Published by Springer Science and Business Media LLC in European Journal of Clinical Pharmacology
- Vol. 76 (12), 1623-1630
- https://doi.org/10.1007/s00228-020-02963-4
Abstract
Aim The COVID-19 pandemic caused by infection with the novel coronavirus SARS-CoV-2 is urging the scientific community worldwide to intense efforts for identifying and developing effective drugs and pharmacologic strategies to treat the disease. Many of the drugs that are currently in (pre)clinical development are addressing late symptoms of the disease. This review focuses on potential pharmacologic intervention at an early stage of infection which could result in less-infected individuals and less cases with severe COVID-19 disease due to reduced virus entry into the cells. Method We scanned the literature for evidence on drugs that target the virus entry machinery into host cells and consist mainly of ACE2 and TMPRSS2, as well as other cellular molecules regulating ACE2 expression, such as ADAM-17 and calmodulin. Results Several drugs/drug classes have been identified. Most of them are already used clinically for other indications. They include recombinant soluble ACE2, indirect ACE2 modulators (angiotensin receptor blockers, calmodulin antagonists, selective oestrogen receptor modifiers), TMPRSS2 inhibitors (camostat mesylate, nafamostat mesylate, antiandrogens, inhaled corticosteroids) and ADAM-17 enhancers (5-fluorouracil). Conclusion Several agents have potential for prophylactic and therapeutic intervention at the early stages of SARS-CoV-2 infection and COVID-19 disease and they should be urgently investigated further in appropriate preclinical models and clinical studies.Keywords
This publication has 40 references indexed in Scilit:
- SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease InhibitorCell, 2020
- Pharmacologic Treatments for Coronavirus Disease 2019 (COVID-19)JAMA, 2020
- Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic targetIntensive Care Medicine, 2020
- A pilot clinical trial of recombinant human angiotensin-converting enzyme 2 in acute respiratory distress syndromeCritical Care, 2017
- Pharmacokinetics and Pharmacodynamics of Recombinant Human Angiotensin-Converting Enzyme 2 in Healthy Human SubjectsClinical Pharmacokinetics, 2013
- Calmodulin interacts with angiotensin‐converting enzyme‐2 (ACE2) and inhibits shedding of its ectodomainFEBS Letters, 2007
- Tumor Necrosis Factor-α Convertase (ADAM17) Mediates Regulated Ectodomain Shedding of the Severe-acute Respiratory Syndrome-Coronavirus (SARS-CoV) Receptor, Angiotensin-converting Enzyme-2 (ACE2)Online Journal of Public Health Informatics, 2005
- Human coronavirus NL63 employs the severe acute respiratory syndrome coronavirus receptor for cellular entryProceedings of the National Academy of Sciences of the United States of America, 2005
- Receptor and viral determinants of SARS-coronavirus adaptation to human ACE2The EMBO Journal, 2005
- Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirusNature, 2003