Introduction
Inhibitors of the viral RNA synthesis
Remdesivir (Veklury®)
Favipiravir
Other RdRp inhibitors: sofosbuvir, galidesivir
Lopinavir
Other PIs
Various antiviral agents
Human recombinant soluble ACE2 (APN01)
Camostat (Foipan®)
Umifenovir
Oseltamivir
Hydroxychloroquine (HCQ) and chloroquine (CQ)
Monoclonal Antibodies and Convalescent Plasma
Casirivimab plus Imdevimab (REGN-COV2)
Bamlanivimab, Etesevimab
Other mAbs, some key papers:
Antibody fragments, nanobodies
Convalescent plasma (passive immunization)
Immunomodulators
Corticosteroids
Interferons
Introduction
Let’s face it: after one year of intensive research, we have some steroids which have been shown to reduce mortality in patients with severe COVID-19 (see Corticosteroids, page 24); and we have one approved drug, remdesivir (Veklury®), which had a marginal benefit in a company-sponsored trial (Beigel 2020). There are also a few monoclonal antibodies, showing modest effects on viral load. And the JAK inhibitor baricitinib, in combination with remdesivir, in special patient populations. That’s the COVID-19 treatment armamentarium as of January 2021.
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1. Inhibitors of the viral RNA synthesis
SARS-CoV-2 is a single-stranded RNA betacoronavirus. Potential targets are some non-structural proteins such as protease, RNA-dependent RNA polymerase (RdRp) and helicase, as well as accessory proteins. Coronaviruses do not use reverse transcriptase. There is only a total of 82% genetic identity between SARS-CoV and SARS-CoV-2. However, the strikingly high genetic homology for one of the key enzymes, the RdRp which reaches around 96%, suggests that substances effective for SARS may also be effective for COVID-19.
RdRp inhibitors
Remdesivir (Veklury®)
Remdesivir (RDV) is a nucleotide analog and the prodrug of an adenosine C nucleoside which incorporates into nascent viral RNA chains, resulting in premature termination. It received an “Emergency Use Authorization” from the FDA in May and a so-called “conditional marketing” authorization from the EMA in July.
Favipiravir
Favipiravir is another broad antiviral RdRp inhibitor that has been approved for influenza in Japan (but was never brought to market) and other countries. Favipiravir is converted into an active form intracellularly and recognized as a substrate by the viral RNA polymerase, acting like a chain terminator and thus inhibiting RNA polymerase activity (Delang 2018). In the absence of scientific data, favipiravir has
Other RdRp inhibitors: sofosbuvir, galidesivir
Some other RdRp inhibiting compounds have also been discussed. Sofosbuvir is a polymerase inhibitor which is also used as a direct-acting agent in hepatitis C. It is usually well tolerated. Modelling studies have shown
Protease inhibitors (PIs)
A promising drug target is the viral main protease Mpro, which plays a key role in viral replication and transcription. Some HIV PIs have been extensively studied in COVID-19 patients.
Lopinavir
Lopinavir/r is thought to inhibit the 3-chymotrypsin-like protease of coronaviruses. To achieve appropriate plasma levels, it has to be boosted with another HIV PI called ritonavir (usually indicated by “/r”: lopinavir/r). Due to some uncontrolled trials in SARS and MERS, lopinavir/r was…
Other PIs
For another HIV PI, darunavir, there is no evidence from either cell experiments or clinical observations that the drug has any prophylactic effect (De Meyer 2020).
It is hoped that the
2. Various antiviral agents
Most coronaviruses attach to cellular receptors via their spike (S) protein. Within a few weeks after the discovery of SARS-CoV-2, several groups elucidated the entry of the virus into the target cell (Hoffmann 2020, Zhou 2020). Similar to SARS-CoV, SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2) as a key receptor, a surface protein that ….
Human recombinant soluble ACE2 (APN01)
HrsACE2 is a therapeutic candidate that neutralizes infection by acting as a decoy. It may act by binding the viral spike protein (thereby neutralizing SARS-CoV-2) and by interfering with the renin–angiotensin system. APN01 has been shown to be safe and well-tolerated in a total of 89 healthy volunteers and…
Camostat (Foipan®)
In addition to binding to ACE2, priming or cleavage of the spike protein is also necessary for viral entry, enabling the fusion of viral and cellular membranes. SARS-CoV-2 uses the cellular protease transmembrane protease serine 2 (TMPRSS2). Compounds inhibiting this protease may therefore inhibit viral entry (Kawase 2012). The TMPRSS2 inhibitor camostat, approved in Japan for the treatment of chronic pancreatitis (trade name Foipan®), may block the cellular entry of SARS-CoV-2 (Hoffmann 2020). Clinical data are pending. Some trials are ongoing, mostly in mild-to-moderate disease.
Umifenovir
Umifenovir (Arbidol®) is a broad-spectrum antiviral drug approved as a membrane fusion inhibitor in Russia and China for the prophylaxis and treatment of influenza. Chinese guidelines recommend it for COVID-19 – according to a Chinese press release it is able to inhibit the replication of SARS-CoV-2 in low concentrations of 10-30 μM (PR 2020). In a small retrospective and uncontrolled study in mild to moderate COVID-19 cases, 16 patients who were treated with oral umifenovir 200 mg TID and lopinavir/r were compared with 17 patients who had received lopinavir/r as monotherapy for 5–21 days (Deng 2020). At day 7 in the combination group, SARS-CoV-2 nasopharyngeal specimens became negative in 75%, compared to 35% with lopinavir/r monotherapy. Chest CT scans were improving for 69% versus 29%, respectively. Similar results were seen in another retrospective analysis (Zhu 2020). However, a clear explanation for this remarkable benefit was not provided. Another retrospective study on 45 patients from a non-intensive care unit in Jinyintan, China failed to show any clinical benefit (Lian 2020). There is a preliminary report of a randomized study indicating a weaker effect of umifenovir compared to favipiravir (Chen 2020).
Oseltamivir
Oseltamivir (Tamiflu®) is a neuraminidase inhibitor that is approved for the treatment and prophylaxis of influenza in many countries. Like lopinavir, oseltamivir has been widely used for the current outbreak in China (Guan 2020). Initiation immediately after the onset of symptoms may be crucial. Oseltamivir is best indicated for accompanying influenza co-infection, which has been seen as quite common in MERS patients at around 30% (Bleibtreu 2018). There is no valid data for COVID-19. It is more than questionable whether there is a direct effect in influenza-negative patients with COVID-19 pneumonia. SARS-CoV-2 does not require neuramidases to enter target cells.
Hydroxychloroquine (HCQ) and chloroquine (CQ)
HCQ is an anti-inflammatory agent approved for certain autoimmune diseases and for malaria. The story of HCQ in the current pandemic is a warning example of how medicine shouldn’t work.
3. Monoclonal Antibodies and Convalescent Plasma
The development of highly successful monoclonal antibody-based therapies for cancer and immune disorders has created a wealth of expertise and manufacturing capabilities. As long as all other therapies fail or have only modest effects, monoclonal antibodies are the hope for the near future. There is no doubt that antibodies with high and broad
Casirivimab plus Imdevimab (REGN-COV2)
The antibodies given to Trump. Casivirimab (REGN10933) binds at the top of the RBD, extensively overlapping the binding site for ACE2, while the epitope for imdevimab (REGN10987) is located on the side of the RBD, away from the REGN10933 epitope, and has little to no overlap with
Bamlanivimab, Etesevimab
Bamlanivimab (LY-CoV555, BAM) from Lilly is a neutralizing IgG1 monoclonal antibody (mAb) directed against the spike protein of SARS-CoV-2. On 9 November, the FDA issued an emergency use authorization (EUA) for the treatment of mild to moderate COVID-19 in patients who are 12 years of age and older weighing at least 40 kilograms, and who are at high risk for progressing to severe COVID-19 and/or hospitalization
Other mAbs, some key papers:
- The first report of a human monoclonal antibody that neutralizes SARS-CoV-2 (Wang 2020). 47D11 binds a conserved epitope on the spike RBD explaining its ability to cross-neutralize SARS-CoV and SARS-CoV-2, using a mechanism that is independent of receptor-binding inhibition. This antibody could be useful for development of antigen detection tests and serological assays targeting SARS-CoV-2.
- From 60 convalescent patients, 14 potent neutralizing antibodies were identified by
Antibody fragments, nanobodies
- Antibody domains and fragments such as VH (heavy chain variable domain, 15 kDa) are attractive antibody formats for candidate therapeutics. They may have better
Convalescent plasma (passive immunization)
Human convalescent plasma (CP) could be a rapidly available option for prevention and treatment of COVID-19 disease when there are sufficient numbers of people who have recovered and can donate immunoglobulin-containing serum (Casadevall 2020). Passive immune therapy appears to be
4. Immunomodulators
While antiviral drugs are most likely to prevent mild COVID-19 cases from becoming severe, adjuvant strategies will be needed, particularly in severe cases.
Corticosteroids
Corticosteroids are thus far the only drugs which provide a survival benefit in patients with severe COVID-19. During the first months of the pandemic, according to current WHO guidelines, steroids were controversially discussed and were not recommended outside clinical trials.
Interferons
The interferon (IFN) response constitutes the major first line of defense against viruses. This complex host defense strategy can, with accurate understanding of its biology, be translated into safe and effective antiviral therapies. In a recent comprehensive review, the recent progress in our understanding of both type I and type III IFN-mediated innate antiviral responses against human coronaviruses is described (Park 2020).
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