Repurposing the mucolytic cough suppressant and TMPRSS2 protease inhibitor bromhexine for the prevention and management of SARS-CoV-2 infection
Maggio et al.,
Repurposing the mucolytic cough suppressant and TMPRSS2 protease inhibitor bromhexine for the prevention and..,
Pharmacol Res., doi:10.1016/j.phrs.2020.104837 (Review)
Proposal to use bromhexine for prophylaxis and treatment of COVID-19 based on TMPRSS2 inhibition, widespread clinical use, and supporting pharmacokinetic and safety data.
Maggio et al., 22 Apr 2020, peer-reviewed, 2 authors.
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Pharmacological Research 157 (2020) 104837
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Letter to the Editor
Repurposing the mucolytic cough suppressant and TMPRSS2 protease inhibitor bromhexine for the
prevention and management of SARS-CoV-2 infection
Dear Editor,
Bromhexine is an over-the-counter mucolytic cough suppressant
that was introduced in 1963 under the trademark of Bisolvon®. It is a
widely prescribed drug for treatment of a range of respiratory conditions, mainly those associated with a disturbance of mucus secretion,
and it is well tolerated and safe. Chemical library screening for discovery of suppressors of prostate cancer metastasis identified bromhexine as a potent and selective inhibitor of the TMPRSS2
(Transmembrane Protein Serine 2) protease displaying an IC50 of
0.75 μM [1]. This is important since TMPRSS2 is an androgen regulated
cell-surface serine protease that belongs to the very few trypsin-like
proteases expressed in the human respiratory tract. It plays a role in the
proteolytic activation and invasion of the human airway epithelium by
influenza [2] as well as SARS-CoV and MERS [3] viruses.
The spread of the COVID-19 coronavirus pandemic is a major crisis of
public health and has stimulated intensive efforts to find treatments active
against the SARS-CoV-2 virus. Hoffmann et al. [4] proposed the TMPRSS2
serine protease inhibitor camostat mesylate [5], a drug approved in Japan
for use in chronic pancreatitis, for off-label treatment of SARS-CoV-2-infected patients. Their proposal is grounded in the finding that SARS-CoV-2
cell entry depends on binding of the viral spike (S) protein to cellular
angiotensin converting enzyme 2 receptor and priming of the S protein by
host cell TMPRSS2 protease [4]. Hoffmann’s study indicated that cleavage
of the viral S protein by TMPRSS2 protease occurs at S1/S2 arginine rich
multibasic site: this is prevented by camostat mesylate which accordingly
inhibits the entry of SARS-CoV-2 virus into Calu-3 lung cell lines and
primary human airway epithelial cells. Furthermore, based on studies of
influenza and other coronaviruses, TMPRSS2 may also regulate viral assembly in the Golgi apparatus and release of SARS-CoV-2-from the plasma
membrane as previously suggested by Shen et al. [6].
The interaction of bromhexine with the TMPRSS2 enzyme together
with its widespread clinical use and safety strongly support its evaluation in
patients with SARS-CoV-2 infection, especially since the use of camostat
mesylate is much less well established and very expensive. Indeed, bromhexine was already proposed by Shen et al. [6] as a candidate drug..
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