Potential new treatment strategies for COVID-19: is there a role for bromhexine as add-on therapy?

Abstract

Of huge importance now is to provide a fast, cost-effective, safe, and immediately available pharmaceutical solution to curb the rapid global spread of SARS-CoV-2. Recent publications on SARS-CoV-2 have brought attention to the possible benefit of chloroquine in the treatment of patients infected by SARS-CoV-2. Whether chloroquine can treat SARS-CoV-2 alone and also work as a prophylactic is doubtful. An effective prophylactic medication to prevent viral entry has to contain, at least, either a protease inhibitor or a competitive virus ACE2-binding inhibitor. Using bromhexine at a dosage that selectively inhibits TMPRSS2 and, in so doing, inhibits TMPRSS2-specific viral entry is likely to be effective against SARS-CoV-2. We propose the use of bromhexine as a prophylactic and treatment. We encourage the scientific community to assess bromhexine clinically as a prophylactic and curative treatment. If proven to be effective, this would allow a rapid, accessible, and cost-effective application worldwide.

Keywords: Bromhexine; COVID-19; Prophylactic; Protease inhibitor; SARS-CoV-2; Treatment.

Fig. 1

Schematic of the SARS-CoV-2 genome organization and virion. This CoV genome comprises a 5′-untranslated region (5′-UTR), open-reading frames (ORFs) 1a and 1b encoding nonstructural proteins 3-chymotrypsin-like protease (3CLpro), papain-like protease (PLpro), helicase (Hel), and RNA-dependent RNA polymerase (RdRp) as well as accessory proteins, and the structural S protein (S), E protein (E), M protein (M), and N phosphoprotein (N)

Fig. 2

SARS-CoV-2 S protein primary structure. The S protein consists of two subunits: The S1 subunit contains a signal peptide, followed by an N-terminal domain (NTD) and receptor-binding domain (RBD). The S1 domain is responsible for receptor binding and rests above the other subunit, the C-Terminal S2, containing conserved fusion peptide (FP), heptad repeat (HR) 1 and 2, transmembrane domain (TM), and cytoplasmic domain (CP), responsible for fusion of viral and cellular membranes [10]

Fig. 3

Host–virus interaction: how we can exploit these mechanisms to treat SARS-CoV-2 using bromhexine and/or hydroxychloroquine (HCQ) and/or quercetin. SARS-CoV-2 employs two routes for host cell entry, which are dependent on the localization of the proteases required for activation of the S protein. Binding of SARS-CoV-2 to the cellular receptor, ACE2, can result in uptake of virions into endosomes, where the S protein is activated by the pH-dependent cysteine protease cathepsin B/L. Activation of the S protein by cathepsin B/L can be blocked by HCQ and quercetin. Alternatively, the S protein can be activated by TMPRSS2, resulting in fusion of the viral membrane with the plasma membrane. Activation of the S protein by TMPRSS2 can be blocked by bromhexine. Quercetin also blocks viral replication via inhibition of the viral cysteine protease 3CLpro. ( Adapted from Simmons et al. [24])