|Adapted from Science 367(6485), 1412-1413 (2020).|
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), previously known as 2019 Novel Coronavirus (2019-nCoV), is a positive-sense, single-stranded RNA virus that causes the potentially lethal COVID-19 respiratory tract infection. This new virus belongs to the genus Betacoronavirus, which also includes SARS-CoV and MERS-CoV. The first case of COVID-19 was detected in December, 2019 in Wuhan, China, and has now been declared a pandemic (1). Human-to-human spread has been confirmed, with a suspected incubation period of ~2-14 days. There are some reports of transmission in the absence of clear symptoms, though infected people are likely most contagious due to coughing and sneezing that expel respiratory droplets.
With SARS-CoV-2 now reaching pandemic status, researchers and clinicians have been working furiously to learn more about the virus’s biology and pathogenesis as well as how to treat the more clinically aggressive COVID-19 cases. As with any viral pathogen, understanding how SARS-CoV-2 enters host cells is of great significance.
In their study published very recently in Cell, Hoffmann et al. confirm findings reported by Zhou et al. that angiotensin-converting enzyme 2 (ACE2) is the cellular receptor for SARS-CoV-2, as it is for SARS-CoV (2, 3). In addition, they identify the serine protease TMPRSS2 as a critical factor in the priming of the SARS-CoV-2 spike (S) protein, an essential step for viral entry into host cells through fusion of the viral and cellular membranes. The authors also demonstrate that the serine protease inhibitor camostat mesylate, an agent that has already seen clinical application as a treatment for chronic pancreatitis in Japan, is able to interfere with SARS-CoV-2 infection of lung cells. Finally, the study presents data that antibodies generated to SARS-CoV S protein may have some protective activity against SARS-CoV-2. Together, this work expands our knowledge of key factors involved in SARS-CoV-2’s entry into cells and reveals some promising avenues for SARS-CoV-2-directed therapies.
To further expedite the identification of agents with activity against SARS-CoV-2, the WHO’s SOLIDARITY study will assess the potential utility of four different classes of clinically known drugs or drug combinations against the virus (4). The four arms include the viral polymerase inhibitor remdesivir, the anti-malarial agents chloroquine and hydroxychloroquine, the HIV protease inhibitors lopinavir and ritonavir, and lopinavir/ritonavir with interferon-beta. This study, which is one of many ongoing trials that are reviewing more than a dozen possible therapies, is stripped down to accelerate data acquisition and be accessible to physicians everywhere. The central focus of many of these trials is to evaluate existing agents with acceptable safety profiles (e.g., the serine protease inhibitor camostat mesylate) that are amenable to repurposing for use against SARS-CoV-2. In addition, compounds previously found to have activity against SARS-CoV, MERS-CoV, or other viruses are being reexamined, as is the use of convalescent plasma from recovered COVID-19 patients and monoclonal antibodies targeting viral components (5). The singular determination to fight this virus as a world community is now widely appreciated as the only path to eventual success.
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