COVID-19 Drug Discovery and Development – Why Diverse Strategies Are Critical

“There is no silver bullet at the moment, and there might never be,” said World Health Organization Director-General Tedros Adhanom at a virtual press conference at the beginning of August. While it was this bleak sound bite that made the headlines, Tedros also had words of praise for the progress made towards identifying treatments that aid the recovery of COVID-19 patients with the most serious forms of the disease.

Research towards treatments for COVID-19 has been developing at a phenomenal speed, even though it feels as though solutions can’t come soon enough; the widespread transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has had significant health, economic and social impacts across the globe, and as of September 8^th more than 27 million cases and 890,000 deaths have been recorded in 188 countries.

Research groups across the world have set about identifying drugs for the treatment of COVID-19, by screening both novel and existing drugs for their ability to alleviate symptoms and stem viral replication. Here, we provide an update on ongoing global efforts to develop and test drugs for the treatment of COVID-19 and explore the range of strategies being employed.

Treatments for COVID-19: Highlights to date

Before delving into the various strategies of COVID-19 drug development, here is an overview of drugs which have made headlines in recent months:

Drug name/class	Mechanism of action	Stage of disease	Comment
Dexamethasone/glucocorticoid	Produces a myriad of effects including general anti-inflammatory actions which may modulate inflammation-mediated lung injury	Lower 28-day mortality observed in patients who received dexamethasone and respiratory support (invasive mechanical ventilation or oxygen alone)	The first drug shown to save lives, however dexamethasone did not reduce mortality in those who were not receiving respiratory support. Beneficial effects depend on dosage, timing, and patient selection. Low cost, widely available.
Remdesivir/broad spectrum antiviral	A metabolite of remdesivir inhibits viral RNA polymerases	Adults and adolescents from 12 year of age with pneumonia who require supplemental oxygen	Emergency use authorization awarded. May reduce recovery time in those with severe disease, certainty of evidence is low. Controlled trials are ongoing.
Hydroxychloroquine/antimalarial, disease-modifying antirheumatic drug	Multiple effects including: reduced cytokine production, inhibits immune activation. Also interferes with lysosomal activity and membrane stability	Usage in settings of COVID-19 not advised due to adverse events including serious cardiac events, hepatitis and renal failure	Public figures generated a staggering amount of hype about hydroxychloroquine, despite the lack of efficacy data.
Lopinavir (antiretroviral protease inhibitor) and ritonavir (improves bioavailability of lopinavir)	Block the action of enzymes critical to HIV replication	The RECOVERY trial concluded there is no beneficial effect of lopinavir/ritonavir for patients hospitalized with COVID-19	Used to treat HIV-1 infection.

COVID-19 therapies are coming from all angles

Ideally, if there was a fire, the fire brigade would be wearing fire-resistant protective clothing and recruiting every firefighter in town. Locals would be moving away from the fire and making water sources available. Others would be creating firebreaks to prevent the spread, while those living further away would be establishing landscape management strategies to minimize the fire threat. It appears that fighting SARS-CoV-2 will require a similar approach. As Tedros says, we need to “do it all”.

COVID-19 is a disease which can leave you with anything between a mild sniffle to an unpleasant combination of high fever, heavy fatigue, and lung inflammation and damage. The drivers of clinical symptoms can be roughly divided into two categories: the virus itself and the hyperinflammatory response to the virus that occurs in the most severely ill people. Consequently, efforts to identify appropriate treatments are often focused on one category, and sometimes, a particular patient group or stage of disease. Given the nature of COVID-19, it is highly likely that a combination of drugs (“drug cocktail”) will be needed to both neutralize the virus and suppress the symptoms of COVID-19. Antiviral treatments may target viral components directly, or other cellular processes involved in viral infection or replication. To date, interventional studies for COVID-19 have attempted to achieve a wide range of goals, including:

• Prevent SARS-CoV-2 from entering lung epithelial cells
• Help manage the disease with general anti-inflammatory drugs
• Assess the efficacy of drugs as post-exposure prophylaxis
• Evaluate the rate of co-infections among COVID-19 critically ill
• Reduce symptoms by targeting inflammatory mediators (with a humanized anti-interleukin-6 receptor monoclonal antibody, tocilizumab)
• Prevent hypercoagulation

When time is of the essence: The rationale for repurposing

A vaccine for COVID-19 is unlikely to be available anytime soon and millions of people continue to be affected every day. To reduce the burden of disease on individuals and society, effective treatments for COVID-19 are urgently needed. The current global situation has yielded many scientists towards the most rapid screening approaches including the repurposing of known, approved drugs. Drug repurposing is not a new concept; many compounds progress through the drug development process (approved for safety and optimized for bioavailability) only to be dropped at the very end for showing a marginal clinical benefit, or due to an unfavorable market landscape. If successful, the repurposing of drugs for COVID-19 could enable earlier treatment access for patients at a significantly lower developmental cost.

A number of world-class research groups have joined forces and received significant funding grants to support their rapid search for appropriate FDA-approved drugs. For example, the Wyss Institute at Harvard University, alongside the Icahn School of Medicine at Mount Sinai and the University of Maryland School of Medicine, have established a drug testing pipeline with the help of $16 million from the United States’ Defense Advanced Research Projects Agency (DARPA). Meanwhile, a National Institutes of Health (NIH)-funded study has emerged in Nature, reporting the discovery of SARS-CoV-2 antiviral drugs through large-scale compound repurposing following a collaborative effort from researchers across the US, Hong Kong and Austria, some of whom share their insights on their experiences in the video below.

Meet the scientists on the frontline with coronavirus. Video credit: Sanford Burnham Prebys Medical Discovery Institute

Large-scale repurposing efforts yield anti-SARS-CoV-2 compounds

In a bid to identify molecules with antiviral activity against SARS-CoV-2, Riva et al. systematically sifted through the open-access ReFRAME (Repurposing, Focused Rescue, and Accelerated Medchem) library, one of the world’s largest collections of small molecules that have been either FDA-approved or registered outside of the US, entered clinical trials or undergone significant preclinical characterization. Sumit Chanda, director and professor at the Infectious and Inflammatory Diseases Center, Sanford Burnham Prebys Medical Discovery Institute, describes the process as a funneling strategy, where they work with increasingly relevant cell lines and animal models to identify the most promising candidates that could be assessed in the more expensive and time-consuming clinical trials.

Of the ~12,000 compounds screened, 100 inhibited SARS-CoV-2 replication in mammalian cells, 21 of which did so in a dose-response fashion. Achieving a sufficiently high dose concentration to elicit antiviral effects in vivo was predicted to be practical and possible for 13 of these compounds – based on EC₅₀ values in various cell lines. The most potent of these were evaluated for antiviral activity in human induced pluripotent stems cell (iPSC)-derived pneumocyte-like cells (five candidates) and in an ex vivo lung culture system (one candidate). The latter candidate is called apilimod, a small molecule inhibitor of an enzyme (phosphoinositide 5-kinase or PIKfyve, an endosomal lipid kinase) important to the endocytic pathway in which SARS-CoV-2 “travels” along during its journey through the cell. Encouragingly, apilimod potently antagonized viral replication in these tissues, and the findings are in agreement with those of another research group. This month, Kang et al. published an article in PNAS, describing the potent inhibition of SARS-CoV-2 by apilimod, providing further evidence to suggest PIKfyve-inhibition as a potential strategy that could limit infection and disease pathogenesis. The authors also noted that apilimod has passed safety tests in previous clinical trials for nonviral indications.

Chanda highlights the incredible pace at which this work was produced. Typically, a project like this would take years, rather than months. He points out that by wanting to do something quickly, there were sacrifices (and not just weekends). For example, they ran with the assay and the cell lines that allowed them to produce results quickly. “This is the reason we put the entire dataset out there… not one/three/20 molecules, we put all 100 molecules out there. These are the ones we found because of our experimental system, but please keep testing the others because you’ll probably find other things that work,” said Chanda.

De novo design still has its place

The de novo development of new drugs is expected to be more time- and cost-intensive than drug repurposing efforts. Regardless, effective therapeutic options for SARS-CoV-2 would still be valuable in the future and would help extend world-wide drug supplies for COVID-19. Dr Xiaoqiang Huang, research investigator in the Yang Zhang Lab at the Department of Computational Medicine and Bioinformatics at the University of Michigan’s Medical School is the lead author of a recent article published in Aging, titled “De novo design of protein peptides to block association of the SARS-CoV-2 spike protein with human ACE2”. Huang believes it is possible to get designer peptides to the market in the next few years, partly because of the relatively low immunogenicity of peptide drugs. Huang says that “This may make it easier for peptides to pass safety tests in clinical trials with a reduced development period. Besides, the technologies for synthesizing peptides are developing rapidly, which can also accelerate the development of designer peptide drugs.” Huang and his co-authors also highlight another advantage of peptide drugs; in comparison to small molecules, they can be more effective at blocking protein-protein interactions by specifically binding to the interface binding region.

To design multiple peptide sequences that can competitively bind to the SARS-CoV-2 receptor binding domain, the University of Michigan research group used a protein design system called EvoDesign.“EvoDesign is the first de novo protein design protocol developed in our lab; it performs design simulation by combining the evolution-based information collected from protein databases and an accurate physics- and knowledge-based energy function, namely EvoEF2, for computing atomic interactions such as van der Waals forces, electrostatics, hydrogen bonding, and desolvation energies,” said Huang.

Overall, these sophisticated computational tools represent a promising new avenue for the de novo development of drug discovery studies.

The COVID-19 treatment toolbox is one piece to the puzzle

Getting the global pandemic under control will require a number of puzzle pieces to come together, including vaccines, drugs, and potentially, cell therapies for COVID-19 – not to mention global social and political cooperation. Scientists around the world are working tirelessly to identify drugs that they hope will be added to the COVID-19 toolbox. Chanda provides some perspective on hopes for the future: “I agree there's not going to be a silver bullet, but there are going to be continual improvements… people are thinking that it will be like the day after the World War, where everyone's going to go out into the streets and start kissing strangers! That's just not going to happen. This is going to be an incremental thing. The best thing we can do, and the most effective thing we can do, is social distance and wear a mask. This is by far better than any vaccine and any drug, and in the immediate-term, it’s going to be what gets us out of this.”

Michele Wilson is a freelance science writer for Choice Science Writing.