The 2019 novel coronavirus (2019-nCoV) has spread rapidly since its identification in patients with severe pneumonia in Wuhan, China. As of 14 February 2020, 2019-nCoV has been reported in 25 countries across 4 continents and >60,000 cases have been confirmed, with an estimated mortality risk of ~2%.
Characteristics of 2019-nCoV
2019-nCoV is an enveloped, positive-sense, single-stranded RNA β-coronavirus. Similar to SARS and MERS, the 2019-nCoV genome encodes structural proteins, non-structural proteins and accessory proteins. Initial analyses of genomic sequences from 2019-nCoV show that the catalytic sites of the four 2019-nCoV enzymes that can represent antiviral targets are highly conserved, and share a high level of sequence similarity with the corresponding SARS and MERS enzymes. Besides, protein structural analyses indicate that key drug-binding pockets in viral enzymes are probably conserved across 2019-nCoV, SARS and MERS. Therefore, it is reasonable to consider repurposing existing MERS and SARS inhibitors for 2019-nCoV.
Potential candidates for 2019-nCoV
Given the scale and rapid spread of 2019-nCoV acute respiratory diseases, drugs that work are urgently needed before vaccines can be produced. Based on experience with the treatment of two other infections caused by human coronaviruses (SARS-CoV and MERS-CoV), the researchers focuses on the potential to reuse antiviral agents that have been approved or are being developed to treat infections caused by hepatitis B virus (HBV), hepatitis C virus (HCV), HIV, and influenza viruses. The results were published as a Comment article in the journal Nature Reviews Drug Discovery under the title "Therapeutic options for the 2019 novel coronavirus (2019-nCoV)".
Approved nucleoside analogues (ribavirin and favipiravir) and experimental nucleoside analogues (remdesivir and galidesivir) may have potential against 2019-nCoV. Nucleoside analogues in the form of adenine or guanine derivatives target the RNA-dependent RNA polymerase and block viral RNA synthesis in a broad spectrum of RNA viruses, including human coronaviruses. Remdesivir (GS-5734) is a phosphoramidate prodrug of an adenine derivative with a chemical structure similar to that of tenofovir alafenamide, an approved HIV reverse transcriptase inhibitor. Remdesivir has broad-spectrum activities against RNA viruses such as SARS and MERS in cell cultures and animal models, and has been tested in a clinical trial for Ebola. Two phase III trials (NCT04252664 and NCT04257656) were initiated in early February 2020 to evaluate intravenous remdesivir in patients with 2019-nCoV, with estimated completion dates in April 2020.
Baricitinib as potential treatment for 2019-nCoV
For 2019-nCoV, researchers from BenevolentAI in the UK search for approved drugs that may be useful, focusing on those that may prevent the viral infection process. They identified baricitinib and predicted it would reduce the virus' ability to infect lung cells. The relevant research results were published in the journal Lancet and the title of the paper was "Baricitinib as potential treatment for 2019-nCoV acute respiratory disease".
Most viruses enter cells through receptor-mediated endocytosis. The receptor that 2019-nCoV uses to infect lung cells may be ACE2. As a cell surface protein, ACE2 exists on the surface of the kidney, blood vessels, and heart cells. Importantly, it also exists on the surface of AT2 alveolar epithelial cells. These AT2 cells are particularly vulnerable to virus infection. One of the known regulators of endocytosis is AP2-associated protein kinase 1 (AAK1). Destruction of AAK1 may in turn disrupt access to cells and intracellular assembly of viral particles.
Of the 378 AAK1 inhibitors in this knowledge map, 47 have been approved for medical use and 6 have high affinity to inhibit AAK1. They include many anti-tumor drugs, such as sunitinib and erlotinib, both of which inhibit the virus from infecting cells by inhibiting AAK1. However, these two compounds have serious side effects, and the data from these researchers conclude that they are effective in inhibiting AAK1 at high doses. They believe that these drugs are not a safe remedy for sick and infected people.
In contrast, one of the six high-affinity binding AAK1 drugs is the JAK kinase inhibitor baricitinib, which also binds to cyclin G-related kinases. Given that the baricitinib concentration in plasma is sufficient to inhibit AAK1 when administered at a therapeutic dose (once daily, 2 mg or 4 mg each), these researchers suggest that clinical trials may be performed using a suitable population of 2019-nCoV patients to reduce viral invasion and inflammation in patients. Of course, these early investigations and recommendations require further detailed research and analysis, and should not be relied on as constituting any kind of medical or other advice or recommendation.
References
- Guangdi Li et al. Therapeutic options for the 2019 novel coronavirus (2019-nCoV). Nature Reviews Drug Discovery, 2020.
- Peter Richardson et al. Baricitinib as potential treatment for 2019-nCoV acute respiratory disease. Lancet, 2020,