Identification And Development Of Therapeutics For COVID-19

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Halie M. Rando,a,b,c Nils Wellhausen,a Soumita Ghosh,d Alexandra J. Lee,a Anna Ada Dattoli,e Fengling Hu,f James Brian Byrd,g Diane N. Rafizadeh,h,i Ronan Lordan,j Yanjun Qi,k Yuchen Sun,k Christian Brueffer,l Jeffrey M. Field,e Marouen Ben Guebila,m Nafisa M. Jadavji,n,o Ashwin N. Skelly,h,p Bharath Ramsundar,q Jinhui Wang,r Rishi Raj Goel,p YoSon Park,a COVID-19 Review Consortium, Simina M. Boca,s,t Anthony Gitter,u,v Casey S. Greeneb,c,e,w

The COVID-19 pandemic is a rapidly evolving crisis. With the worldwide sci- entific community shifting focus onto the SARS-CoV-2 virus and COVID-19, a large num- ber of possible pharmaceutical approaches for treatment and prevention have been pro- posed. What was known about each of these potential interventions evolved rapidly throughout 2020 and 2021. This fast-paced area of research provides important insight into how the ongoing pandemic can be managed and also demonstrates the power of interdisciplinary collaboration to rapidly understand a virus and match its characteristics with existing or novel pharmaceuticals. As illustrated by the continued threat of viral epi- demics during the current millennium, a rapid and strategic response to emerging viral threats can save lives. In this review, we explore how different modes of identifying can- didate therapeutics have borne out during COVID-19.

KEYWORDS COVID-19, review, therapeutics

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LESSONS FROM PRIOR HCoV OUTBREAKS

At first, SARS-CoV-2’s rapid shift from an unknown virus to a significant worldwide threat closely paralleled the emergence of Severe acute respiratory syndrome-related co- ronavirus 1 (SARS-CoV-1), which was responsible for the 200222003 SARS epidemic. The first documented case of COVID-19 was reported in Wuhan, China, in November 2019, and the disease quickly spread worldwide in the early months of 2020. In com- parison, the first case of SARS was reported in November 2002 in the Guangdong Province of China, and it spread within China and then into several countries across continents during the first half of 2003 (3, 8, 9). In fact, genome sequencing quickly revealed the virus causing COVID-19 to be a novel betacoronavirus closely related to SARS-CoV-1 (10).

While similarities between these two viruses are unsurprising given their close phy- logenetic relationship, there are also some differences in how the viruses affect humans. SARS-CoV-1 infection is severe, with an estimated case fatality rate (CFR) for SARS of 9.5% (8), while estimates of the CFR associated with COVID-19 are much lower, at up to 2% (1). SARS-CoV-1 is highly contagious and spread primarily by droplet trans- mission, with a basic reproduction number (R0) of 4 (i.e., each person infected was esti- mated to infect four other people) (8). There is still some controversy whether SARS- CoV-2 is primarily spread by droplets or is primarily airborne (11–14). Most estimates of its R0 fall between 2.5 and 3 (1). Therefore, SARS is thought to be a deadlier and more transmissible disease than COVID-19.

With the 17-year difference between these two outbreaks, there were major differ- ences in the tools available to efforts to organize international responses. At the time that SARS-CoV-1 emerged, no new HCoV had been identified in almost 40 years (9). The identity of the virus underlying the SARS disease remained unknown until April of 2003, when the SARS-CoV-1 virus was characterized through a worldwide scientific effort spearheaded by the World Health Organization (WHO) (9). In contrast, the SARS- CoV-2 genomic sequence was released on 3 January 2020 (10), only days after the international community became aware of the novel pneumonia-like illness now known as COVID-19. While SARS-CoV-1 belonged to a distinct lineage from the two other HCoVs known at the time of its discovery (8), SARS-CoV-2 is closely related to SARS-CoV-1 and is a more distant relative of another HCoV characterized in 2012, Middle East respiratory syndrome-related coronavirus (MERS-CoV) (15, 16). Significant efforts had been dedicated toward understanding SARS-CoV-1 and MERS-CoV and how they interact with human hosts. Therefore, SARS-CoV-2 emerged under very dif- ferent circumstances than SARS-CoV-1 in terms of scientific knowledge about HCoVs and the tools available to characterize them.

POTENTIAL APPROACHES TO THE TREATMENT OF COVID-19

Therapeutic interventions can utilize two approaches: they can mitigate the effects of an infection that harms an infected person, or they can hinder the spread of infec- tion within a host by disrupting the viral life cycle. The goal of the former strategy is to reduce the severity and risks of an active infection, while for the latter, it is to inhibit the replication of a virus once an individual is infected, potentially freezing disease pro- gression. Additionally, two major approaches can be used to identify interventions that might be relevant to managing an emerging disease or a novel virus: drug repur- posing and drug development. Drug repurposing involves identifying an existing com- pound that may provide benefits in the context of interest (17). This strategy can focus on either approved or investigational drugs, for which there may be applicable preclin- ical or safety information (17). Drug development, on the other hand, provides an op- portunity to identify or develop a compound specifically relevant to a particular need, but it is often a lengthy and expensive process characterized by repeated failure (18). Drug repurposing therefore tends to be emphasized in a situation like the COVID-19 pandemic due to the potential for a more rapid response.

Even from the early months of the pandemic, studies began releasing results from analyses of approved and investigational drugs in the context of COVID-19. The rapid timescale of this response meant that, initially, most evidence came from observational studies, which compare groups of patients who did and did not receive a treatment to determine whether it may have had an effect. This type of study can be conducted rap- idly but is subject to confounding. In contrast, randomized controlled trials (RCTs) are the gold standard method for assessing the effects of an intervention. Here, patients are prospectively and randomly assigned to treatment or control conditions, allowing for much stronger interpretations to be drawn; however, data from these trials take much longer to collect. Both approaches have proven to be important sources of infor- mation in the development of a rapid response to the COVID-19 crisis, but as the pan- demic draws on and more results become available from RCTs, more definitive answers are becoming available about proposed therapeutics. Interventional clinical trials are currently investigating or have investigated a large number of possible therapeutics and combinations of therapeutics for the treatment of COVID-19 (Fig. 1).

The purpose of this review is to provide an evolving resource tracking the status of efforts to repurpose and develop drugs for the treatment of COVID-19. We highlight four strategies that provide different paradigms for the identification of potential phar- maceutical treatments. The WHO guidelines (20) and a systematic review (21) are com- plementary living documents that summarize COVID-19 therapeutics.

REPURPOSING DRUGS FOR SYMPTOM MANAGEMENT

A variety of symptom profiles with a range of severity are associated with COVID-19 (1). In many cases, COVID-19 is not life-threatening. A study of COVID-19 patients in a hospital in Berlin, Germany, reported that the highest risk of death was associated with infection-related symptoms, such as sepsis, respiratory symptoms such as ARDS, and cardiovascular failure or pulmonary embolism (22). Similarly, an analysis in Wuhan, China, reported that respiratory failure (associated with ARDS) and sepsis/multiorgan failure accounted for 69.5% and 28.0% of deaths, respectively, among 82 deceased patients (23). COVID-19 is characterized by two phases. The first is the acute response, where an adaptive immune response to the virus is established and in many cases can mitigate viral damage to organs (24). The second phase characterizes more severe cases of COVID-19. Here, patients experience a cytokine storm, whereby excessive pro- duction of cytokines floods into circulation, leading to systemic inflammation, immune dysregulation, and multiorgan dysfunction that can cause multiorgan failure and death if untreated (25). ARDS-associated respiratory failure can occur during this phase. Cytokine dysregulation was also identified in patients with SARS (26, 27).

In the early days of the COVID-19 pandemic, physicians sought to identify potential treatments that could benefit patients, and in some cases shared their experiences and advice with the medical community on social media sites such as Twitter (28). These on- the-ground treatment strategies could later be analyzed retrospectively in observational studies or investigated in an interventional paradigm through RCTs. Several notable cases involved the use of small-molecule drugs, which are synthesized compounds of low molec- ular weight, typically less than 1 kDa (29). Small-molecule pharmaceutical agents have been a backbone of drug development since the discovery of penicillin in the early twentieth century (30). It and other antibiotics have long been among the best-known applications of small molecules to therapeutics, but biotechnological developments such as the prediction of protein-protein interactions (PPIs) have facilitated advances in precise targeting of spe- cific structures using small molecules (30). Small-molecule drugs today encompass a wide range of therapeutics beyond antibiotics, including antivirals, protein inhibitors, and many broad-spectrum pharmaceuticals.

APPROACHES TARGETING THE VIRUS

Therapeutics that directly target the virus itself holds the potential to prevent people infected with SARS-CoV-2 from developing potentially damaging symptoms (Fig. 3). Such drugs typically fall into the broad category of antivirals. Antiviral therapies hinder the spread of a virus within the host, rather than destroying existing copies of the virus, and these drugs can vary in their specificity to a narrow or broad range of viral targets. This process requires inhibiting the replication cycle of a virus by disrupting one of six fundamental steps (69). In the first of these steps, the virus attaches to and enters the host cell through endocytosis. Then the virus undergoes uncoating, which is classically defined as the release of viral contents into the host cell. Next, the viral genetic mate- rial enters the nucleus where it is replicated during the biosynthesis stage. During the assembly stage, viral proteins are translated, allowing new viral particles to be assembled. In the final step, new viruses are released into the extracellular environ- ment. Although antivirals are designed to target a virus, they can also impact other processes in the host and may have unintended effects. Therefore, these therapeutics must be evaluated for both efficacy and safety. As the technology to respond to emerging viral threats has also evolved over the past 2 decades, a number of candidate treatments have been identified for prior viruses that may be relevant to the treatment of COVID-19.

Many antiviral drugs are designed to inhibit the replication of viral genetic material during the biosynthesis step. Unlike DNA viruses, which can use the host enzymes to propagate themselves, RNA viruses like SARS-CoV-2 depend on their own polymerase, the RNA-dependent RNA polymerase (RdRP), for replication (71, 72). RdRP is therefore a potential target for antivirals against RNA viruses. Disruption of RdRP is the proposed mechanism underlying the treatment of SARS and MERS with ribavirin (73). Ribavirin is an antiviral drug effective against other viral infections that was often used in combina- tion with corticosteroids and sometimes interferon (IFN) medications to treat SARS and MERS (9). However, analyses of its effects in retrospective and in vitro analyses of SARS and the SARS-CoV-1 virus, respectively, have been inconclusive (9). While IFNs and riba- virin have shown promise in in vitro analyses of MERS, their clinical effectiveness remains unknown (9). The current COVID-19 pandemic has provided an opportunity to assess the clinical effects of these treatments. As one example, ribivarin was also used in the early days of COVID-19, but a retrospective cohort study comparing patients who did and did not receive ribivarin revealed no effect on the mortality rate (74).

Since nucleotides and nucleosides are the natural building blocks for RNA synthesis, an alternative approach has been to explore nucleoside and nucleotide analogs for their potential to inhibit viral replication. Analogs containing modifications to nucleo- tides or nucleosides can disrupt key processes, including replication (75). A single incorporation does not influence RNA transcription; however, multiple events of incor- poration lead to the arrest of RNA synthesis (76). One candidate antiviral considered for the treatment of COVID-19 is favipiravir (Avigan), also known as T-705, which was discovered by Toyama Chemical Co., Ltd. (77). It was previously found to be effective at blocking viral amplification in several influenza virus subtypes as well as other RNA viruses, such as Flaviviridae and Picornaviridae, through a reduction in plaque forma- tion (78) and viral replication in Madin-Darby canine kidney cells (79). Favipiravir (6-flu- oro-3-hydroxy-2-pyrazinecarboxamide) acts as a purine and purine nucleoside analog that inhibits viral RNA polymerase in a dose-dependent manner across a range of RNA viruses, including influenza viruses (80–84). Biochemical experiments showed that favi- piravir was recognized as a purine nucleoside analog and incorporated into the viral RNA template. In 2014, the drug was approved in Japan for the treatment of influenza that was resistant to conventional treatments like neuraminidase inhibitors (85). Though initial analyses of favipiravir in observational studies of its effects on COVID-19 patients were promising, recent results of two small RCTs suggest that it is unlikely to affect COVID-19 outcomes (Appendix).

In contrast, another nucleoside analog, remdesivir, is one of the few treatments against COVID-19 that has received FDA approval. Remdesivir (GS-5734) is an intrave- nous antiviral that was proposed by Gilead Sciences as a possible treatment for Ebola virus disease. It is metabolized to GS-441524, an adenosine analog that inhibits a broad range of polymerases and then evades exonuclease repair, causing chain termination (86–88). Gilead received an emergency use authorization (EUA) for remdesivir from the FDA early in the pandemic (May 2020) and was later found to reduce mortality and re- covery time in a double-blind, placebo-controlled, phase 3 clinical trial performed at 60 trial sites, 45 of which were in the United States (89–92). Subsequently, the WHO Solidarity trial, a large-scale, open-label trial enrolling 11,330 adult inpatients at 405 hospitals in 30 countries around the world, reported no effect of remdesivir on in-hos- pital mortality, duration of hospitalization, or progression to mechanical ventilation (93). Therefore, additional clinical trials of remdesivir in different patient pools and in combination with other therapies may be needed to refine its use in the clinic and determine the forces driving these differing results. Remdesivir offers proof of principle that SARS-CoV-2 can be targeted at the level of viral replication, since remdesivir tar- gets the viral RNA polymerase at high potency. Identification of such candidates depends on knowledge about the virological properties of a novel threat. However, the success and relative lack of success, respectively, of remdesivir and favipiravir underscore the fact that drugs with similar mechanisms will not always produce similar results in clinical trials.

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