Overview of Antiviral Drug Therapy for COVID-19: History
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Contributor:
Renata Esposito
,
Davida Mirra
,
Liberata Sportiello
,
Giuseppe Spaziano
,
Bruno D'agostino

The vaccine weapon has resulted in being essential in fighting the COVID-19 outbreak, but it is not fully preventing infection due to an alarming spreading of several identified variants of concern. In fact, the recent emergence of variants has pointed out how the SARS-CoV-2 pandemic still represents a global health threat. Moreover, oral antivirals also develop resistance, supporting the need to find new targets as therapeutic tools. However, cocktail therapy is useful to reduce drug resistance and maximize vaccination efficacy. Natural products and metal-drug-based treatments have also shown interesting antiviral activity, representing a valid contribution to counter COVID- 19 outbreak. This report summarizes the available evidence which supports the use of approved drugs and further focuses on significant clinical trials that have investigated the safety and efficacy of repurposing drugs and new molecules in different COVID-19 phenotypes. To date, there are many individuals vulnerable to COVID-19 exhibiting severe symptoms, thus characterizing valid therapeutic strategies for better management of the disease is still a challenge.

  • COVID-19
  • Antiviral drugs
  • Natural agents
  • Immune system
  • Approved drugs

1. Introduction

A pandemic outbreak caused by COVID-19 disease has infected and killed over six million people so far due to the high infectiousness rate, representing one of the main threats nowadays [1]. The genomic instability of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with constant mutation hindered the strain characterization, promoting the fast spread and consequently a public health crisis [2][3]. Indeed, the virus quickly changes for adapting itself to different environments, developing several mutations associated with multiple variants that compromise the efficacy of the vaccines [4][5]. All of this sheds light on an emerging concern, stressing the urgent need to develop safe and effective therapeutic agents for COVID-19 treatment. In this scenario, researchers and physicians from all over the world have been joining their resources to slow down the virus’s spread, developing new antiviral drugs for SARS-CoV-2 and/or testing the anti-COVID efficacy of old drugs by a drug repurposing approach [6][7][8]. The pharmacological treatment targets virus and host proteins to counter viral entry and replication and immune system factors involved in the inflammatory reaction [9]. Currently, the latest COVID-19 treatment guidelines report monoclonal antibodies as prophylactic and therapeutic methods for preventing virus entry into host cells [10] and antiviral drugs to use in the early stage of the disease to act directly on viral replication [11]. Moreover, the cytokine rise associated with lung and systemic inflammation supports the use of immunomodulants to fight the cytokine storm developing into the severe phenotypes of COVID-19 [12][13][14][15]. Finally, adjuvant therapy has proved useful for reinforcing the host’s immune response against infection [16][17]. Unfortunately, despite the availability of several drug treatments and more effective vaccines, the SARS-CoV2 circulation has not yet been stopped; conversely, it is spreading at an accelerated rate. So, new targets and mechanisms to decline the viral load should be found.

2. Therapeutic Agents Approved in COVID-19 Therapy

2.1. Monoclonal Antibodies (mAbs)

In the field of a COVID-19 tailored approach, mAbs play an important role in restoring immune homeostasis by a fast and passive immunity response that aids in the destruction of infected cells with the reduction of the viral load [18]. They represent an effective and viable therapy and/or prophylaxis option against COVID-19, associated with a lowering of hospitalizations and death rates, obtaining an emergency authorization for treating mild to moderate COVID-19 subjects [19]. Most of the mAbs targeted the epitopes distributed over S glycoprotein (spike) (S1 and S2) with a high binding affinity by hindering viral entry. In fact, SARS-CoV-2 enters host cells by its spike to bind to the angiotensin-converting enzyme 2 (ACE2) receptor, widely expressed in the respiratory tract [20]. Unlike host proteins, spike is highly mutable and the administration of mAbs against it strictly depends on the circulating variants [21]. In fact, newly emerging SARS-CoV-2 variants harboring mutations can mask the function of neutralizing antibodies, making them less effective [22][23]. The first mAbs approved by FDA are bamlanivimab, casirivimab and imdevimab associated with a lower incidence of hospitalization, emergency department visits and death than the placebo. Overall, their use is well-tolerated and contraindicated in critical patients [24]. Due to emerging variants, the food and drug administration (FDA) has given emergency approval for the mAbs combinations bamlanivimab with etesevimab (BAM/ETE) and casirivimab with imdevimab (REGEN-COV) since the frequency of variants resistant to the mAbs cocktail is lower than a single treatment. Many clinical trials have showed that BAM/ETE and REGEN-COV treatment of COVID-19 outpatients induced improved clinical and virologic outcomes when compared with untreated controls. Notably, the interim analysis of an ongoing clinical trial described the safety and efficacy of REGN-COV in the first 275 non-hospitalized patients with COVID-19. The results revealed the efficacy of the REGN-COV antibody cocktail in enhancing viral clearance and reducing medically attended visits. Interestingly, REGN-COV showed a major efficacy in serum antibody-negative patients or when viral load was higher at baseline [25]. Moreover, a retrospective cohort study determined the real-world effectiveness of REGEN-COV against COVID-19-related hospitalization, severe disease and death [26]. The effectiveness of REGEN-COV was 56.4% in preventing COVID-19 hospitalization, 59.2% in preventing severe COVID-1 and 93.5% in preventing COVID-19 death in the 28 days after treatment. Data suggest that the benefits are greater when REGEN-COV is administered within the first five days following infection. These results were related to Delta variant patients, unlike the Omicron variant which results in less susceptibility. In fact, the Omicron variant (BA.1 lineage) lost susceptibility to the BAM/ETE and REGEN-COV [27]. The spread of the SARS CoV-2 omicron lineages changed the landscape of mAbs activity with respect to previous virus variants. In fact, the emerging BA.2, BA.3, BA.4 and BA.5 lineages showed a 7-16-fold reduction in susceptibility against Sotrovimab, a monoclonal antibody that targets a highly conserved epitope in the receptor binding domain (RBD) of SARS-CoV-2 [21]. Moreover, a recent multinational, placebo-controlled, randomized clinical ACTIV-3 trial investigated the neutralizing activity of sotrovimab and the two-antibody cocktails “BRII-196 plus BRII-198” in hospitalized COVID-19 patients, and showed no efficacy for improving clinical outcomes [28]. Therefore, the resistance phenomenon and discouraging clinical results led the authorities to remove its EUA (5 April 2022). Currently, the administration of BAM/ETE, CAS/IMD and sotrovimab is not recommended due to the lack of activity against the dominating omicron lineages. The only mAbs that preserve activity against predominant omicron variants are tixagevimab/cilgavimab and bebtelovimab as described in correspondence by Daichi Yamasoba and colleagues [29]. In fact, bebtelovimab is the only one that has shown remarkably preserved in vitro activity against all SARS-CoV-2 variants, including the omicron variant and the most recent dominant BA.4 and BA.5 subvariants [30]. The pan efficacy of bebtelovimab was also reported by the phase II BLAZE-4 trial (NCT04634409) that promoted the Emergency Use Authorization (EUA) for early treatment of COVID-19 outpatients by the FDA in February 2022. The EUA by EMA is ongoing. Finally, the use of bebtelovimab became important especially when antiviral nirmatrelvir-ritonavir is contraindicated [31][32]. Overall, mAbs reduced disease progression by approximately 70 to 85% against mild-to-moderate COVID-19 patients [18] but intravenous or subcutaneous administration represents a barrier to their use in a health care setting. However, constant monitoring of variants of concern is compulsory due to the rapid evolution of the epidemiological scenario.

2.2. Antiviral Agents

Since the beginning of the pandemic, antiviral drugs have been used in COVID-19 therapy for hindering the viral replicative cycle at different levels and in different ways. The available antiviral drugs target viral or host proteins necessary for virus burden persistence [9]. Overall, they are most effective in the early stages of the disease and are characterized by viral proliferation, unlike critical phenotype where inflammatory reaction dominates. Notably, oral antivirals should be delivered within five days after the onset of COVID-19 symptoms to ensure efficacy. Thus, their delayed administration easily results in the worst effectiveness [33].

2.2.1. RNA-Dependent RNA Polymerase (RdRp) Inhibitors

The first licensed antiviral agents for COVID-19 were remdesivir and molnupiravir. They were approved for emergency use by the FDA to treat outpatients with mild COVID-19 phenotype and risk factors for progression to severe stages of the disease. Remdesivir is a non-canonical nucleotide able to stop the chain-elongation reaction of the viral RNA by RNA-dependent RNA polymerase (RdRp). Literature data gathered so far support the efficacy of intravenous remdesivir in reducing the risk and the length of hospitalization showing efficacy against several SARS-CoV-2 strains [34]. The “WHO Solidarity randomized trial” investigated the efficacy of remdesivir in inpatients with COVID-19. Notably, 8275 patients were randomized to remdesivir or its control; mortality and hospitalization were chosen as primary and secondary outcomes, respectively. Overall mortality was 602 (14.5%) in patients receiving remdesivir with respect to 643 (15.6%) in the control group. A sub-analysis focused on the disease severity revealed that among the severe COVID-19 patients, 151 (42.1%) of 359 in treatment with remdesivir died compared to 134 (38.6%) of 347 in the control group. Of the patients receiving oxygen support, 14.6% assigned to remdesivir died versus 16.3% assigned to control [35]. All these data showed a major efficacy of remdesivir in mild-to-moderate patients supporting the use of antivirals immediately following the onset of symptoms. Therefore, the current guidelines recommend remdesivir for unvaccinated ambulatory patients and vaccinated outpatients at risk for vaccine failure or at high risk for progression to severe disease within 7 days of symptom onset. The prodrug molnupiravir also inhibits RNA-polymerase of SARS-CoV-2 and other RNA viruses but presents a high mutational power in RNA strand, unlike remdesivir. Indeed, molnupiravir metabolization produces the cytidine nucleoside analogue N-hydroxycytidine (NHC) which is phosphorylated to the active form N-hydroxycytidine-5′-triphosphate (NHC-TP) into the cells. NHC monophosphate acts as a competitive substrate that will be incorporated by the SARS-CoV-2 viral RdRp introducing mutations (G to A and C to U substitution) in the viral genome and consequently inhibiting viral replication [36][37]. The literature reports a higher antiviral activity of molnupiravir than remdesivir, likely due to the high binding stability of NHC monophosphate to RNA viral which prevents its removal by exonucleases. EUA was based on data from 1734 randomized mild-to-moderate COVID-19 participants, recruited in phase III MOVe-OUT trial. The study investigated the efficacy and safety of molnupiravir (800-mg) compared to placebo, delivered within 5 days of the onset of symptoms. Molnupiravir showed superiority over placebo in preventing hospitalization or death (7.3% versus 14.1%, respectively) [38]. Nowadays, molnupiravir is licensed for adult unvaccinated outpatients and mild-to-moderate COVID-19 vaccinated patients at risk for vaccine failure, within 5 days from symptoms onset. However, molnupiravir use has not been recommended in international guidelines or is only recommended when no other treatment options exist due to its lower reported effectiveness at preventing hospitalization compared to other outpatient therapies.

2.2.2. Protease Inhibitors

M protease (Mpro) and PL protease (PLpro), respectively known as nsp5 and nsp3, are essential enzymes in the virus replication cycle, representing a therapeutic target to prevent the success of the infection. They process the virus polyproteins into active proteins and differ from human proteases, promoting the lower toxicity of protease inhibitors [39]. Notably, nirmatrelvir (NM) is an oral protease inhibitor that is active by cleaving the 2 viral polyproteins; it is available in association with ritonavir®, a strong cytochrome P450-3A4 inhibitor, that increases nirmatrelvir concentrations reducing the dose regimen and the side effects of the antiviral. Recent reports found that nirmatrelvir-ritonavir (NM/r) reduced the risk of death and hospitalization, showing more efficacy than molnupiravir. Moreover, data derived from the EPIC-HR trial (Evaluation of Protease Inhibition for COVID-19 in High-Risk Patients) evaluating the efficacy of nirmatrelvir in non-hospitalized subjects without previous immunity against SARS-CoV-2 provided significant results on which the FDA EUA was based. The trial was performed when the delta variant was the predominant variant [40][41]. A real-world interesting study was next carried out, based on data obtained from electronic medical records of the Israeli population. The aim of this work was to assess the effectiveness of NM/r in reducing the rate of hospitalizations in COVID-19 subjects when the omicron variant was the most common variant. The results corroborated the efficacy of NM/r in preventing severe COVID-19 onset, above all among adults 65 years of age or older [42]. Overall, all these studies brought to light the importance to start NM/r treatment in early COVID-19 to prevent the worsening of the illness towards severe disease and quickly reduce SARS-CoV-2 viral load. Unfortunately, viral mutations represent the hot-spot for achieving successful therapy, probably responsible for the virological and clinical rebound in patients receiving NM/r as described by Charness et al. [43]. Notably, the mechanisms involved in COVID-19 recrudescence after NM/r treatment were investigated, suggesting that reduced target drug concentrations related to pharmacokinetic changes and/or insufficient therapy length were involved [44]. Moreover, some mutations in the Mpro have been revealed such as alanine 260 to threonine (A260T) or valine (A260V) in samples of patients receiving NM/r but did not cause a reduction in Mpro activity [45]. Overall, the occurrence frequency of rebound illness is unclear, but increases in viral load were detected in 1 to 2% of participants in the phase III clinical trial [46]. However, the mechanisms of COVID-19 recrudescence after treatment are still to be investigated. Currently, NMV/r is licensed for adult unvaccinated outpatients and vaccinated outpatients at risk for vaccine failure and/or progression to severe disease within 5 days of symptom onset.

3. Natural Products and Metal-Based Drugs as Adjuvants Agents in COVID-19 Control

To curb newly emerging SARS CoV2 variants, many plant metabolites may be valid alternatives against SARS-CoV-2. Among natural metabolites, alkaloids have potential drug activity by intercalation power against nucleic acids (DNA or RNA), stabilizing them in single-stranded form. Homoharringtonine (HHT) is a cytotoxic plant alkaloid [47] strongly targeting the mRNA translation; its interesting antiviral activity promoted a protocol for clinical trials of HHT nebulization on COVID-19 patients has been registered (ChiCTR-2100045993) by the Ditan Hospital [48]. Moreover, clinical trials and observational studies showed the positive effects of alkaloids colchicine and emetine in COVID-19 subjects [49][50][51][52]. Carvacrol (CARV) is an essential oil extract derived from different plants which exerted antioxidant, antiviral and Ca2+ influx modulator activities. Notably, Javed et al. reported a potential action in COVID-19, showing its potential inhibition activity of ACE2 and Mpro with a significant block in the host cell entry and replication of SARS-CoV-2 (Figure 2) [53][54]. Different research groups discovered the in vitro and in vivo anti-SARS-CoV-2 activity of cepharanthine, a natural alkaloid extracted from Stephania japonica. Cepharanthine have antioxidant and anti-inflammatory properties [55][56] and could exert an antiviral effect by modulating Hypoxia-inducible factor-1 (HIF-1), a dysregulated factor in COVID-19 [57]. Recently, a high antiviral activity of cepharanthine against SARS-CoV-2 was identified, also preserving antiviral action against the Beta (B.1.351) variant. Thus, a phase II clinical study (NCT05398705) of cepharantine was completed in mild COVID-19 patients but the results are not posted yet. Finally, the LINCOLN survey showed the beneficial effects of Vitamin C and L-Arginine in long-COVID [58][59][60] with significantly less severe long-COVID symptoms and a better effort perception when compared to the alternative treatment group [61]. Overall, natural products represent an important tool in fighting COVID-19 but their use is only recommended in mild-to-moderate stages of the disease. Similarly, natural products as well as metal-based molecules may be valid tools for combating COVID-19. Phase II clinical trials are ongoing to evaluate the efficacy of ebselen (SPI-1005) in mild and severe COVID-19 patients (NCT04484025/NCT04483973). Ebselen is a synthetic organoselenium with a glutathione peroxidase function which exhibits in vitro antiviral activity against SARS-CoV-2 [62][63][64]. Iron level alterations are also detected in COVID-19 patients, related to oxidative stress. Therefore, iron chelators such as deferasirox, deferoxamine and deferiprone could be beneficial in decreasing cytotoxicity and oxidative stress damage associated with hyperferritinemia [65]. Among them, deferiprone seems to be the most potent antioxidant drug in vitro, in vivo and in clinical models of COVID-like diseases, supporting its potential therapeutical use [66][67].

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