This article was the 2nd place winner in the Labroots Writing contest. Congrats Ayon!
According to WHO situation report published on 2nd July 2020 more than 105 million cases of coronavirus disease 2019 (COVID-19) has been reported worldwide with a mortality rate of over 5 million. In such situations drug discovery becomes challenging as routinely it is lengthy and expensive process, and further the journey gets tougher when several variants of coronavirus gets detected such as severe acute respiratory syndrome coronavirus (SARS-CoV) first detected from Wuhan, China 2019, middle eastern respiratory syndrome related coronavirus (MERS-CoV), and currently the novel coronavirus (SARS-CoV-2). Therefore, to battle the time constraints in drug development and obtain expedited ethical approval, the drug regulatory authorities such as USFDA have granted permission for expedited drug development, and “Expanded access” clinical trials, which means compassionate use for critical patients where no other alternative treatment exists.
Despite the cooperation from the USFDA and tireless efforts by the researchers, the scientific community is burdened by the unprecedented course and mortality rate of COVID-19, and pressure from stakeholders to bring drugs quickly to the market. There are two strategies on how the scientific community can achieve such a feat. The first strategy is to develop a new chemical entity (NCE), and the second is by repurposing of drugs (identifying new uses of previously approved drugs). Among the two, the second strategy is easier as it is prompt, with lesser documents required to testify the legalities, and economical.
The goal of drug therapy today is to hinder the life cycle of COVID-19 in the host by targeting drugs against any of the six steps such as viral attachment to host cells, viral penetration, viral fusion, biosynthesis, maturation, and viral release. As per evidence from studies, there are several drugs either used or being developed against all the steps but with only relatively fewer drugs against viral release. Additionally, there are also approved adjuvant drugs such as steroids and nutraceuticals to assist in fighting COVID-19.
The novel coronavirus SARS-CoV-2 enters the host cell in two steps. Initially, the virus binds with the spike protein on its surface to host proteins such as angiotensin-converting enzyme 2 (ACE2) or CD147 or CD26 or Dipeptidyl Peptidase-4 (DPP4/DPPIV) or TMPRSS2. Thereafter, cleavage of the spike protein by TMPRSS2 serine protease occurs which exposes the fusion peptide and allows viral entry into the host cell by endocytosis and survive in the low-pH endosomes. Fortunately, we have drugs either used or being developed against all the viral binding sites in the host as explained below.
SARS-CoV-2 infection reduces the expression of angiotensin converting enzyme 2 (ACE2) in the lungs which affects the renin-angiotensin system (RAS) leading to hemodynamic disturbances such as fluid and electrolyte imbalance, blood pressure changes, inflammation, and vascular permeability. ACE2 acts through the Janus kinase pathway. Baricitinib, a Janus kinase (JAK) inhibitor initially approved for rheumatoid arthritis is now under phase II clinical trial (ClinicalTrials.gov number, NCT04320277) for COVID-19. Baricitinib acts against adaptor-associated kinase-1 (AAK1) which is a mediator for the entry of the virus through endocytosis. Currently, delivery of high concentration of soluble ACE2 in infected patients is being experimented.
Protease inhibitors such as Nafamostat mesylate and camostat mesylate (phase II clinical trials: NCT04352400 and NCT04353284 respectively) targeted to TMPRSS2, (a transmembrane protease, serine 2 enzyme) preventing the cleavage of spike protein and viral entry in the host cell are being developed. DPPIV is also known as CD26 and it is a multifunctional cell surface protein that is widely expressed in most cell types including T lymphocytes, bronchial mucosa, and the brush border of proximal tubules and is responsible for the virulence of COVID-19. Presently, the efficacy and safety of DPP-4 Inhibitors in COVID-19 patients with diabetes are being studied (NCT04371978). The CD147 protein is found on activated inflammatory cells and causes the release of cytokines and attracts leukocytes. Meplazumab is a humanized IgG2 monoclonal antibody against CD147 currently being studied on 20 patients with COVID-19 pneumonia in injection form. No adverse effects have been noted in the Meplazumab group. However, the drawback of this trial is the sample size. Previously, humanized anti-CD26 MAb YS110 significantly inhibited MERS-CoV in vitro but currently, the status of this monoclonal antibody is unknown.
Drugs targeting the biosynthesis, replication, and maturation of COVID-19 are very effective to contain the infection. COVID-19 on entering the host cell release viral mRNA which enters the nucleus of the cell and uses the host machinery to synthesize viral proteins. For RNA viruses such as coronavirus, RNA dependent RNA polymerase assists in the synthesis of viral genetic material. This is a very crucial step in the life cycle of COVID-19 and leads to rapidly arising viral mutant forms. Thus, the scientific community decided to develop broad-spectrum antiviral drugs. These broad-spectrum antiviral drugs act against a wide range of viral pathogens and inhibit the biosynthesis and maturation of the virus. Drugs under this category targeting RNA dependent RNA polymerase are Remdesivir (NCT04280705) which is under phase III clinical trials and favipiravir (NCT04402203) is in phase II clinical trials. In the Remdesivir clinical trial the adverse effects noted were similar to placebo and no mortality was reported. Remdesivir has been approved under the “expanded access” treatment protocol for COVID-19 patients (NCT04323761). Galidesivir, Umifenovir (Arbidol) are other drugs in this category under development (NCT03891420). Niclosamide (anti-helminthic drug), Nitazoxanide (anti-parasitic drug) have displayed positive findings in vitro but these drugs need to be validated in animal models, and thereafter clinical trials.
Protease inhibitors such as ritonavir, lopinavir, and indinavir used in HIV was initially an option for COVID-19 but proved ineffective as the nature of protease enzymes are different in HIV and COVID-19, the binding site for HIV protease inhibitors are absent in COVID-19, and lack of efficacy. WHO has recently ordered the discontinuation of Ritonavir/Indinavir and hydroxychloroquine as treatment arms from the Solidarity trial on hospitalized patients in COVID-19 as there was no improvement in mortality rates compared to standard treatment. Tenofovir disoproxil is under clinical trial in Spain (Phase III) in combination with hydroxychloroquine for prophylaxis in healthcare workers (NCT04334928). There are several other anti-retroviral drugs suggested for COVID-19 such as Atazanavir, darunavir, but need confirmatory studies before implementing in practice.
The ubiquitin-proteasome system is an important machinery for viral replication. Thus, antineoplastic agents such as carfilzomib, bortezomib which are proteasome inhibitors have been suggested which not only will reduce the inflammation and viral replication but also will act against the acute respiratory distress syndrome caused due to cytokine storm. However, these drugs need clinical trials before validating the claims. However, contrary evidence was found on mice study revealing that Bortezomib flared the coronavirus infection. Tyrosine kinase inhibitors such as imatinib are currently in clinical trials (NCT04357613) to be used in patients above 70 years old. Imatinib has also demonstrated promising results in vitro as fusion inhibitors for COVID-19.
Chloroquine and hydroxychloroquine are approved antimalarial drug and versatile anti-viral drugs used extensively as they prevent the entry, fusion, replication (translation and post-translational modification), and release of COVID-19 (assembly and budding). Hydroxychloroquine is a soluble and less toxic metabolite of chloroquine with fewer side effects. However, these drugs are toxic and have numerous side effects such as cardiovascular, hepatobiliary, hematological, and immunological. There are several antibiotics/antimicrobials tested for COVID-19 such as hydroxychloroquine, azithromycin, moxifloxacin. Combination therapies such as azithromycin and hydroxychloroquine have shown good results but this combination is proven to be cardiotoxic as it causes QT prolongation in EEG. Recently, the FDA issued a caution to prevent the use of these toxic drugs outside clinical trial settings.
Systemic steroids reduce the systemic manifestations and provide symptomatic relief to COVID-19 patients. Recently, the clinical trials on methylprednisolone have been completed. The results showed significant improvement in laboratory parameters such as C-reactive protein in 7 days, decrease in the no. of patients requiring endotracheal intubation over 28 days, increase in no. of days free from mechanical ventilator over 28 days, and a decrease in the mortality rate over 28 days (NCT04323592). However, due to the lowered blood cells seen in COVID-19, short- and long-term adverse effect, and immunosuppressive effects of steroids, it should be used in the smallest dose and for the shortest duration of time.
The role of immunotherapy against COVID-19 has remained elusive. Blood purification technology has enabled critical patients from reducing the cytokine storm and preventing multiorgan failure. A high dose of intravenous immunoglobulin was administered to 3 patients and all showed clinical improvement and no adverse effects. However, the sample size is too small to validate the claim. Clinical trials on intravenous immunoglobulin are also being conducted and the results are awaited (NCT 04261426). Plasma therapy has proved effective in small clinical trials. However, due to ethical issues, small sample size, sourcing issues, lack of well-planned randomized controlled trials, adverse effects, and lack in efficacy we will have to wait further.
The use of non-steroidal anti-inflammatory drugs such as ibuprofen in COVID-19 is controversial. Some researchers claim that it provides symptomatic relief in COVID-19, dampen the immune system, prolong the shedding of the virus, prevent the disease from being detected apart from the gastrointestinal side effects. Thus, the use of NSAIDS has not been justified to date. Host-directed therapies such as mesenchymal stromal (stem) cell therapy are being developed and USFDA has granted permission for “expanded access” clinical trial to be used in critical patients. The IL-6 inhibitors(tocilizumab, sarilumab), and antibiotics such as trimethoprim and sulfamethoxazole combination have shown phenomenal results in ICU settings with COVID-19 patients. However, to institute them as a treatment modality in COVID-19 patients on a regular basis, the studies on a larger number of patients are needed. Other prospective drugsproposed are Anakirna, CRISPR-Cas13, Colchicine, nitric oxide, ivermectin, lithium, bacillus Calmette-Guerin (BCG), Vitamin D and E and Thymosin.
The exponential increase in COVID-19 worldwide and the simultaneous regulatory restrictions imposed have impacted preclinical and clinical research in several ways. Restricted personnel entry in laboratories and hospitals, limitations in commuting from one place to another, lack of availability of manpower, illness among staff, training people involved in the experiments and trials, site initiation visits, monitoring of trials which were done remotely are a few of the impediments. Dearth in logistic support such as availability of personal protective equipments, and trial-related supplies led to further delays in research. Furthermore, the complexity in the disease pattern of COVID-19, “reversion infections”, COVID-19 in other co-morbid conditions, secondary infection in COVID-19, COVID-19 related complication (venous, arterial and catheter-related thrombotic episodes, thrombocytopenia, lymphocytopenia) differences in response to therapy among different age groups and sex (males (2.8%) and females (1.7%), and the mode of transmission of the virus continue to mystify researchers. Notwithstanding the difficulties, the scientific community has persisted and persevered, with creativity to overcome each pitfall so that we have a plethora of drugs today left only to be validated and instituted in practice.
About the Author
The article is written by Ayon Bhattacharya, M.D., incoming graduate student in the Integrated Biomedical Science Ph.D program. He is interested in the pharmacotherapy of neurological disorders and drug development.
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