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COVID-19 is a form of severe acute respiratory syndrome caused by infection with the coronavirus SARS-CoV-2. COVID-19 emerged in China in late 2019 and rapidly became a global pandemic, prompting an enormous research effort to understand the virus and find treatments. Key areas of research include viral cell entry, viral replication and the hyperactive host immune response, known as cytokine storm. To date only one antiviral drug has been approved for treatment of COVID-19; Remdesivir, a nucleoside analogue inhibiting viral replication.
Figure 1: SARS-CoV-2 Viral Lifecyle. Host cell entry is effected by the binding of receptor binding domain (RBD) of the spike (S) protein on the nucleocapsid to ACE2, a protease on the host cell surface. The binding of the S protein to ACE2 is facilitated by another host cell protease, TMPRSS2 (transmembrane protease, serine 2). Following binding of S protein the virus is internalized. The internalized virus is uncoated and the SARS-CoV-2 genome is released into the cytoplasm. The viral RNA is then replicated and translated. This generates two polyproteins PP1A and PP1AB. These proteins contain within their sequence, papain-like protease (PLpro) and the coronavirus main protease (Mpro, also known as 3CLpro), which cleave the polyproteins into a variety of other functional proteins. The viral RNA also encodes the structural components of the virus, i.e. spike, nucleocapsid, membrane and envelope proteins. Following reproduction of all the viral components, coronavirus is assembled and released via vesicular exocytosis.
Since the emergence of COVID-19, a great deal of research has been carried out to determine the structure of the virus and the mechanisms of infection and replication. Key points in the lifecycle have subsequently been identified as potential prophylactic or therapeutic targets. SARS-CoV-2 is an enveloped positive-sense single-stranded RNA virus contained in a nucleocapsid. One attractive target, within viral cell entry, is the binding of the viral spike protein to the surface receptor ACE2, a host cell membrane protease. ACE2 is highly expressed on epithelial and endothelial cells particularly in the lungs and gastrointestinal tract. Viral proteases associated with viral replication, such as Mpro and PLpro, are also potential targets. In the most severe cases of COVID-19, controlling the disease pathophysiology, synonymous with the cytokine storm, has proved crucial to the host. Regulating the release of interferons, interleukins, tumor-necrosis factors, chemokines, and several other mediators is required for an effective innate immune response and subsequent clearance of infectious agents.
A wide range of approved medicines, have been investigated for their ability to interact with important targets. These efforts have been facilitated by the availability of compound libraries such as the Tocriscreen FDA-Approved Drugs Library (Cat. No. 7200). Other efforts are focusing on identifying new preclinical leads from libraries of bioactive compounds. Collectively these are helping to develop the arsenal of compounds against infectious diseases of this nature.
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