Targeting TMPRSS2 and Cathepsin B/L together may be synergistic against SARS-CoV-2 infection

Abstract

The entry of SARS-CoV-2 into target cells requires the activation of its surface spike protein, S, by host proteases. The host serine protease TMPRSS2 and cysteine proteases Cathepsin B/L can activate S, making two independent entry pathways accessible to SARS-CoV-2. Blocking the proteases prevents SARS-CoV-2 entry in vitro. This blockade may be achieved in vivo through ‘repurposing’ drugs, a potential treatment option for COVID-19 that is now in clinical trials. Here, we found, surprisingly, that drugs targeting the two pathways, although independent, could display strong synergy in blocking virus entry. We predicted this synergy first using a mathematical model of SARS-CoV-2 entry and dynamics in vitro. The model considered the two pathways explicitly, let the entry efficiency through a pathway depend on the corresponding protease expression level, which varied across cells, and let inhibitors compromise the efficiency in a dose-dependent manner. The synergy predicted was novel and arose from effects of the drugs at both the single cell and the cell population levels. Validating our predictions, available in vitro data on SARS-CoV-2 and SARS-CoV entry displayed this synergy. Further, analysing the data using our model, we estimated the relative usage of the two pathways and found it to vary widely across cell lines, suggesting that targeting both pathways in vivo may be important and synergistic given the broad tissue tropism of SARS-CoV-2. Our findings provide insights into SARS-CoV-2 entry into target cells and may help improve the deployability of drug combinations targeting host proteases required for the entry.

Expression of SARS-CoV-2-related receptors in cells of the neurovascular unit: implications for HIV-1 infection

“…In addition, a variety of other molecules have been suggested to be involved in the SARS-CoV-2 internalization into the host cell. Some of them are ADAM17 [ 23 ], DPP4 [ 25 ], AGTR2 [ 27 ], BSG [ 19 ], ANPEP [ 30 ], and cathepsin B/L [ 31 ].…”

“…Once attached, the host infection requires the expression of transmembrane serine protease 2 (TMPRSS2) for priming of the spike protein and viral entry into the cell [ 20 – 22 ]. Along with ACE2 and TMPRSS2, several other molecules have been suggested to participate in SARS-CoV-2 entry into human cells, such as ADAM metallopeptidase domain 17 (ADAM17) [ 23 , 24 ], dipeptidyl peptidase 4 (DPP4) [ 25 , 26 ], angiotensin II receptor type 2 (AGTR2) [ 27 , 28 ], basigin (BSG, also called extracellular matrix metalloproteinase inducer [EMMPRIN] or cluster of differentiation 147 [CD147]) [ 19 , 29 ], aminopeptidase N (ANPEP), [ 30 ], and cathepsin B/L [ 31 , 32 ].…”

Incomplete antiviral treatment may induce longer durations of viral shedding during SARS-CoV-2 infection

“…There are various studies using mathematical models that can explain SARS-CoV-2 infection dynamics and give insight into treatment strategy ( 29 , 42 , 43 , 44 ). Another mathematical study of nasal viral load also showed a longer duration of virus shedding under RDV treatment; however, that study did not directly estimate treatment efficacy ( 45 ).…”

The Transmission of SARS-CoV-2 Infection on the Ocular Surface and Prevention Strategies

“…Teicoplanin is an antibacterial drug that is already in clinical use, and it may also block SARS-CoV-2 entry through the inhibition of CTSL activity [ 122 , 123 ]. Targeting TMPRSS2 and Cathepsin B/L together may be synergistic against SARS-CoV-2 infection [ 124 ].…”