The 2003 SARS outbreak prompted quick research and evaluation of various existing pharmaceuticals. Because of their antiviral properties, chloroquine and nicosamide, initially prescribed as antimalarial and antihelminthic medications, respectively, were repurposed (Cinatl et al., 2003). The potential of luteolin, a naturally occurring flavonoid, glycyrrhizin, hexachlorophene, vanillinbananin, and alpha-Hederin to prevent SARS-CoV replication was investigated. Early attempts to diversify antiviral options were also made with the testing of saponins, valinomycin, and promazine (Cinatl et al., 2003). Another significant discovery from 2003 was the repurposing of penicillium-derived antibiotic mycophenolic acid (MPA), which has shown promise in preventing or minimising coronavirus infection. In 2004, further research led to the discovery of Beta-D-N4-Hydroxycytidine (NHC), which inhibited HCoV-NL63 (EC50 of 400 nM and CC50 of >100 μM) and SARS-CoV (EC50 of 10 μM and CC50 of >100 μM) (Barnard et al., 2004b). Also, an antihelminthic drug, Niclosamide, showed SARS-CoV inhibition at post-entry steps in Vero cells (EC50 of 1–3 μM and CC50 of 250 μM) (Wu et al., 2004). N-(2-aminoethyl)-1 aziridineethanamine (NAAE), a new small-molecule inhibitor (EC50 of 0.5 μM), represented a big step in targeting the SARS-CoV spike protein-mediated cell fusion capabilities (Huentelman et al., 2004). Researchers began to focus on structurally customised inhibitors, such as 2-acetamido-alpha-D- derivatives (Hoever et al., 2005) and Phe-phe-dipeptide inhibitor c(JMF 1521) (Shie et al., 2005), which emerged as potent inhibitors. 2-acetamido-α-D-glucopyranosylamine, benzylcysteine, and Gly-Leu peptide cause an increase of 10-fold to 70-fold in anti-SARS-CoV activity by inhibiting viral entry. Ribavirin (nucleoside analogue of guanosine), which has historically been used to treat Hepatitis C, was tested for its antiviral activity against SARS-CoV in vitro (EC50 of 20 μg/mL and CC50 of >200 μg/mL) (Saijo et al., 2005). Adamantane-based compounds such as Bananins, specifically engineered to inhibit helicase activities and replication of SARS Coronavirus (EC50 of <10 μM and CC50 of 390 μM), were also introduced as promising antiviral agents (Tanner et al., 2005). The emphasis on derivatives remained in 2006; for example, the Eremomycin derivative molecules 27 and 39 (Gan et al., 2006) showed efficacy in blocking viral proteases SARS-CoV (EC50 of 14 μM and CC50 of 22 μM) (Balzarini et al., 2006). In contrast, pyrimidine analogue 6-azauridine emerged as a nucleoside analogue for suppressing HCoV-NL63 replication (EC50 of 32 nM and CC50 of 80 μM) (Pyrc et al., 2006). The antiviral effects of mycophenolic acid (MPA) and ribavirin were confirmed by further characterisation (Barnard et al., 2006). One of the most important factors in preventing viral infections is the suppression of immunological responses, which MPA blocks in vivo by suppressing the apoptosis-inducing enzyme IMP dehydrogenase in the host (BALB/c mice) (Barnard et al., 2006) ( Table 1 ).

Repurposing has been a significant trend throughout the years. A reevaluation of the effectiveness of ribavirin and emodin was performed, with an exploration of the prospect of interferon therapy to augment immune responses against the virus (Åkerström et al., 2007). Ritonavir and Lopinavir were part of the combo therapies offered for SARS-CoV in 2008. Curcumin also became a contender because of its antiviral and anti-inflammatory qualities (Kutluay et al., 2008). By 2010, several novel compounds were introduced, such as Benzopurpurin B, C-473872 and Tetrahydroquinoline Oxocarbazate (Ortiz-Alcantara et al., 2010). A plant-derived protein, Griffithsin, has shown strong efficacy in blocking viral entry (O’Keefe et al., 2010). It became clear that there was a paradigm shift toward exploring remedies that were more natural or drawn from biological sources. SARS-CoV and SARS-CoV-2 are constantly developing, and researchers are continuing their search for effective antiviral medicines. A significant focus exists on both synthetic and natural compounds that may enhance efficacy against the SARS-CoV and hCoV-2 strains ( Table 1 ).

Between 2011 and 2019, the primary emphasis was on the development of new chemicals. This time signified substantial advancements in the comprehension of coronavirus pathophysiology and viral replication processes. This comprehension establishes a vital basis for formulating therapies for the ensuing SARS-CoV-2 epidemic. In 2011, researchers discovered mucroporin-M1, an antimicrobial peptide (AMP) exhibiting antiviral efficacy against the influenza virus (H5N1), measles virus (MeV), and SARS-CoV, signifying a potential foundation for further development (Li et al., 2011). They demonstrated that mucroporin-M1 could inhibit SARS coronavirus entry in HeLa-ACE2 cells with an EC50 of 14.46 μg/mL and a CC50 of 61.58 μg/mL with intense virucidal activity (Li et al., 2011).

By 2012, the antiviral focus had expanded to include molecules such as Scutellarin and Tyr-lys-Tyr-Arg-Tyr-Leu, hexapeptides that showed inhibitory activity against SARS-CoV, HCoV-NL63, and SARS-CoV-2 infection in Vero cells without any cytotoxic effects (Struck et al., 2012). The discovery of protease inhibitors, such as dipeptides dipeptidyl aldehyde (GC373) and dipeptidyl bisulphite adduct salt (GC376), was particularly significant as it targeted the SARS-CoV 3CLpro, with IC50 of 3.48 and 4.35 μM, respectively (Kim et al., 2012). In 2013, three derivatives of N-(9,10-dioxo-9,10-dihydroanthracen-2-yl)benzamide (SSAA09E1), N-[[4-(4-methylpiperazin-1-yl)phenyl]methyl]-1,2-oxazole-5-carboxamide (SSAA09E2), and [(Z)-1-thiophen-2-ylethylideneamino]thiourea (SSAA09E3) were developed. These inhibitors showed activity against SARS-CoV by blocking virus-host cell early interactions at EC50 varying from 3.1-9.7 μM and CC50 varying from 20- 100 μM (Adedeji et al., 2013). Additionally, a peptide, Cyclosporin A, was recognised for its broad-spectrum ability to inhibit diverse SARS-CoV, HCoV-229E and MHV replication or transcription, furthering the exploration of immunosuppressive drugs in antiviral therapy (De Wilde et al., 2011; Pfefferle et al., 2011; De Wilde et al., 2013). 2014 saw the re-emergence of Mycophenolic acid (MPA), a penicillium-derived antibiotic traditionally used as an immunosuppressant. MPA also inhibited MERS-CoV replication in Vero cells with an EC50 of 2.87 μM (Hart et al., 2014). Another compound, Arbidol and its derivatives, a broad-spectrum antiviral used in the treatment of influenza viruses, demonstrates the potential to reduce the SARS-CoV viral load in vitro at 50 μg/mL (Blaising et al., 2014; Hart et al., 2014).

This indicates a growing focus on utilising drugs that have already demonstrated safety for the treatment of SARS-CoV. In 2015, an innovative acyclic sugar scaffold of acyclovir was introduced, demonstrating structural modifications that improved its antiviral properties against coronaviruses, specifically MERS-CoV (EC50 and CC50 of 23 and 71 μM) and HCoV-NL63 (EC50 and CC50 of 8.8 and 120 μM) (Peters et al., 2015). A significant advancement was HIV Tat-protein-derived peptide (YGRKKRRQRRRGSG) known as Tat-P29 (TP29), which demonstrated strong broad-spectrum antiviral activity, effectively inhibiting in vitro replication of SARS-CoV (with an EC50 of 200 μM) and MHV (with an EC50 of 60 μM) (Wang et al., 2015). TP29 negatively affected the 2’-O-MTase activity of nsp10/nsp16, disrupting the replication process of the SARS-CoV genome.

Broad-spectrum coronavirus antiviral medication research advanced in 2016 with numerous promising candidates. Myricetin, a flavonoid, inhibited HCoV-229E and SARS-CoV-2 Mpro and 3CL-Pro enzymes, preventing in vitro replication (Dorman and Dorman, 2016). Nitazoxanide and its derivative, Tizoxanide, displayed broad-spectrum antiviral activities exploited for treating influenza viruses (A and B), as well as Ebola virus (EBOV) (Rossignol, 2016). In vitro studies on LLC-MK2 cells demonstrated that Nitazoxanide could inhibit MERS-CoV with an EC50 of 0.92 μg/mL. Favipiravir, Ribavirin, and Remdesivir have shown effectiveness in inhibiting viral RNA polymerase, indicating significant potential for treating coronavirus (Sissoko et al., 2016). The protease inhibitors Lopinavir-Ritonavir and Nafamostat demonstrated efficacy in inhibiting viral replication by acting on the viral protease (Zumla et al., 2016; Yamamoto et al., 2020).

In 2017, researchers continued to look for antiviral drugs that may stop coronaviruses from replicating. Remdesivir maintained its encouraging performance in preventing viral replication in both in vitro and animal models, whereas Alisparivir and Favipiravir were investigated further for their ability to target RNA polymerase (Furuta et al., 2017; Sheahan et al., 2017). In 2018, the identification of drugs like Saracatinib, a kinase inhibitor, and Disulfiram, typically used for alcohol dependence, broadened the range of repurposed drugs with possible antiviral activity (Shin et al., 2018). Deguelin (9,10-Dimethoxy-3,3-dimethyl-13,13a-dihydro-3H-chromeno[3,4-b]pyrano[2,3-h]chromen-7(7aH)-one) is a natural compound known for its ability to inhibit the HCV replication mechanism. Its potential application in combating SARS-CoV infection underscores the importance of plant-based antivirals (Nukui et al., 2018).

In 2019, these efforts reached a significant point with the additional use of Remdesivir (a nucleoside analogue- GS-5734) and Favipiravir (a purine nucleic acid analogue- T-705). Both compounds demonstrated notable potential in clinical trials and emerged as essential instruments in combating coronaviruses (Mulangu et al., 2019; Declercq et al., 2022). Exploring interference techniques such as interference RNAs (iRNAs) and short interference RNAs (siRNAs) for the treatment of HBV, HCV, HIV, and HTLV infections (Hernández and Sanan-Mishra, 2017) was also found to be a promising antiviral against structural proteins E, M, and N of SARS-CoV. This technique is also potent in antiviral therapies by modulating the host immune response (Li et al., 2011). Overall, the period from 2011 to 2019 laid a strong foundation for developing effective antiviral drugs against SARS-CoV. From 2003 to 2019, a heap of data of in vitro and in vivo antiviral activity assays for several molecules against CoVs was generated. It was high time to critically compare these molecules that could be further investigated for their clinical applicability. The research during these years expanded the antiviral arsenal and provided evidence of the mandatory need for further research and rapid development of broad pharmaceutical agents against emerging viral threats, including the global response to the SARS-CoV-2 pandemic in 2020.

The development of antivirals targeting SARS-CoV-2 had a record-breaking pace during this period ( Table 1 ). Scientists all across the globe have been working hard to find ways to lessen the effects of the virus, develop new vaccinations, and finding new uses for old medications. In order to improve innate immunity against SARS-CoV-2 infections, the present research expanded the spectrum of holistic antiviral techniques by highlighting the relevance of peptide-based antivirals, immunosuppressive drugs, anti-inflammatory molecules, corticosteroids, and natural substances. Additionally, convalescent plasma therapy (CPT)- obtained from previously infected donors who developed antibodies- was further exploited to enhance immune responses in severe COVID-19 cases (Chen et al., 2020). The major challenge in the COVID-19 pandemic was the onset of evolving serotypes and clinical variants across the globe. Therefore, future innovative and diversified antiviral strategies are critically needed for sustained research to combat drug resistance.

Key antiviral agents included Remdesivir (GS-5734), one of the first drugs approved for emergency use, along with other repurposed treatments like Chloroquine, Hydroxychloroquine, Lopinavir/Ritonavir, and Favipiravir, which were tested based on their previous antiviral properties (Dehelean et al., 2020). New molecular candidates were also investigated, such as human monoclonal antibodies (mAbs) 47D11 H2L2-neutralizing Ab, which showed promise in neutralising the SARS-CoV-2 entry in Vero cells with an EC50 of 0.57 μg/mL (Wang et al., 2020). This research opens doors for mAbs that can be used alone or in association with other compounds to treat COVID-19. Peptidomimetic α,β-unsaturated esters, Ebselen, Betulinic acid, and Glycyrrhizic acid were explored for their potential to inhibit viral replication. Various inhibitors targeting the main protease (Mpro) and other essential viral enzymes were developed, including N3, 11a/11b, and Carmofur (Jin et al., 2020; Tiwari et al., 2020). The results of randomised, controlled, and multicenter clinical studies show that immune modulators such as dexamethasone, a corticosteroid, have emerged as essential therapies for decreasing inflammation in severe instances of COVID-19. These treatments have also been shown to considerably reduce death rates in hospitalised patients, according to Recovery 2020 (The RECOVERY Collaborative Group, 2021). Other immunomodulatory agents like tocilizumab, an IL-6 inhibitor, were employed to combat cytokine storms caused by SARS-CoV-2 (Stone et al., 2020; Zeng et al., 2020). The pan-CoV peptide-based fusion inhibitors EK1 and its lipopeptide EK1C4 were also effective against membrane fusion mediated by S proteins of the Omicron subvariants of SARS-CoV-2 and virus-like particle infection. HCoV-OC43’s HR2 region was used to produced peptide EK1 and lipopeptide EK1C4. EK1C4, a lipopeptide with cholesterol and GSGSG-PEG4 linker at its C-terminus, has much higher antiviral effectiveness than EK1.

Several other drugs impairing different stages of viral replication and interfering with nonstructural proteins (NSPs) were explored, such as Camostat Mesylate, Ivermectin, Arbidol Hydrochloride (Umifenovir), Oseltamivir, and Nitazoxanide (Dehelean et al., 2020). Ivermectin of 5 μM concentration inhibited up to 99% of SARS-CoV-2 replication in Vero cells and showed no cytotoxic effects (Caly et al., 2020). The clinical trial studies of Arbidol Hydrochloride (Umifenovir) on COVID-19 patients did not decrease viral load but were still used as an antiviral drug due to its antioxidant potential (Proskurnina et al., 2020). Because vitamin D was also investigated for its ability to strengthen immunological defences, it continued to be used as a medication to treat viral infections (Shalayel et al., 2020).

The year 2021 saw the development and scientific investigation of a number of different antiviral medications in order to combat the worldwide epidemic that was triggered by SARS-CoV-2. Among these medicines, EIDD-2801 (also known as Molnupiravir or MK-4482) has emerged as a potential nucleoside analogue showing considerable activity against SARS-CoV-2 in preclinical models (Wahl et al., 2022). Molnupiravir (EIDD-2801 or MK-4482), which started to treat RNA viruses, has attracted attention for its ability to significantly inhibit SARS-CoV-2 replication (within 48 hours of infection) and transmission, making it a contender for early COVID-19 therapy. Barrigenol, Kaempferol, and Myricetin, extracted from Camelia Sinensis (tea) were discovered in several research (Sharma et al., 2022), also indicated antiviral action. This was mostly due to their capacity to impede viral entrance or reproduction. In order to investigate the therapeutic potential of these plant-based compounds against SARS-CoV-2, the pool of naturally derived medicines that were investigated.

Additionally, throughout the year, continued research was conducted on existing drugs, such as Camostat Mesylate and Ivermectin, to investigate the possibility that these medications may be used to treat SARS-CoV-2 infections. The ability of Camostat Mesylate, a protease inhibitor, to inhibit TMPRSS2, a protein that is necessary for viral entry into host cells, was investigated in this study (Rajter et al., 2021). Likewise, Ivermectin, a standard antiparasitic drug, was examined for its in vitro antiviral properties, although clinical outcomes remained ambiguous (Rajter et al., 2021).

As of the year 2021, Monoclonal antibodies (mAbs) continued to be utilised and researched, marking a significant advancement. It was shown that the combination of REGN10933 and REGN10987, which is known as REGN-COV2, was able to successfully lower the viral load and avoid catastrophic outcomes in COVID-19 patients (Weinreich et al., 2021). Monoclonal antibody therapies continued to play a critical role in the treatment landscape, such as Sotrovimab (VIR-7831 or GSK-4182136)/Bebtelovimab (LY-CoV1404‖ LY3853113) and combinations like Tixagevimab/Cilgavimab and Bamlanivimab/Etesevimab remaining at the forefront. The combination of these MAbs effectively neutralised both the wide-type SARS-CoV-2 and the variants that are now causing concern, including Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), and Delta (B.1.617.2). Additionally, they continued to have significant action against Omicron lineages, such as BA.2.75, BA.4, BA.4.6, and BA.5.

Other monoclonal antibody therapies, such as Casirivimab and Imdevimab, Sotrovimab, and Bamlanivimab with Etesevimab, were also evaluated and used as therapeutic interventions in high-risk patients. The investigation into repurposed drugs persisted in 2021, with compounds like Darunavir (an HIV protease inhibitor), Nitazoxanide (an antiparasitic), and Sorafenib (a cancer therapy) being subjected to clinical trials to assess their antiviral potential (Sun et al., 2021). In addition, Foretinib, Eprosartan, and Inarigivir soproxil were investigated for their capacity to suppress the replication of SARS-CoV-2 and to reduce the severity of the symptoms of infection (Joshi and Poduri, 2021). Dexamethasone and other more recent medications, such as Sarilumab, an IL-6 receptor antagonist, continued to be administered to strengthen the role that immunological modulation performs well against severe COVID-19 (Castelnovo et al., 2021). The findings highlighted the importance of addressing hyperinflammatory syndrome and acute respiratory failure, conditions that were often associated with unfavourable outcomes in patients with severe COVID-19. Innovative agents like P2C-1F11, a neutralising antibody, and CR3022, a monoclonal antibody aimed at the receptor-binding domain of SARS-CoV-2, have offered fresh perspectives on the efficacy of antibody-based therapies in the prevention or treatment of SARS-CoV infections (Atyeo et al., 2021). Finally, naturally derived chemicals such as Aranotin, Ajmalicine, Silymarin, and Ursonic Acid were investigated for their antiviral effects, increasing interest in plant-based and naturally occurring substances for medicinal development against SARS-CoV-2 (Kumar et al., 2021).

The breakthrough development of antiviral drugs for SARS-CoV-2 in 2022 was oral antiviral medicine Paxlovid, a combination of Nirmatrelvir (PF-07321332) with Ritonavir, which emerged as a prominent antiviral therapy for the treatment of COVID-19. This oral treatment significantly reduced the risk of hospitalisation and severe outcomes in high-risk patients when administered early in infection. The Paxlovid leverages the main protease (Mpro) inhibition by Nirmatrelvir and utilises Ritonavir to enhance its pharmacokinetics, with mild side effects. Nirmatrelvir was equally effective as remdesivir, which has been shown to reduce hospitalisation or mortality by 87% in patients with severe COVID-19 (Gottlieb et al., 2022). The efficacy of Paxlovid in lowering viral load established it as a cornerstone in the treatment of COVID-19 arsenal against COVID-19. This highlights a combination therapy trend in antiviral development toward optimising existing medications. Continuing the trend of repurposing existing drugs, the combination of parenteral polymerase inhibitor Remdesivir and Molnupiravir for oral treatment of COVID-19 in non-hospitalised patients was extensively evaluated in 2022. Remdesivir, an already established antiviral agent, demonstrated its ability to reduce the duration of hospitalisation in patients with severe COVID-19.

Inotodiol, neosarcodonin, Dutasteride, Etoposide, and Golvatinib were explored for their potential antiviral properties. Inotodiol, a triterpenoid derived from Inonotus obliquus (I. obliquus), a wild Chaga mushroom, was one of the new compounds whose antiviral and anti-inflammatory efficacy against SARS-CoV-2 was also investigated. Similarly, the well-established anti-inflammatory qualities of neosarcodonin A, B, and C—isolated from Sarcodon scabrosus bitter mushroom—led to its repurposing in light of the rising interest in alternate sources of antiviral compounds. The function of antiandrogens as agents of protection against COVID-19 was also investigated. Under this particular scenario, a double-blind, placebo-controlled randomised clinical trial (RCT) was conducted for dutasteride (DUTA) with early antiandrogen therapy (EAT) was recommended as a treatment for COVID-19 (EAT-DUTA AndroCoV). Etoposide, a medication that contains epipodophyllotoxin, has been used to treat immune-mediated inflammatory illnesses linked to cytokine storm syndrome for over 40 years. This molecule has been investigated for COVID-19 treatment. The most significant binding free energy is exhibited by golvatinib (IC50 around 1uM), indicating that it may be evaluated for anti-SARS-CoV-2 infection in vitro (Shen et al., 2023).

Simeprevir, a protease inhibitor and Paritaprevir authorised for managing HCV infection, has shown potential antiviral efficacy at EC50 of 1.41 ± 0.12 μM to suppress SARS-CoV-2 replication in Vero E6 cells (Muturi et al., 2022). Ivermectin, tipranavir, and paritaprevir have dose-dependent inhibitory action (IC50) against protease (3CLPro) at 21.5, 27.7, and 73.4 µM, indicating their potential as anti-SARS-CoV-2 inhibitors (Mody et al., 2021). Furthermore, in silico investigations on alpha-ergocryptine and diosgenin glucoside revealed inhibitory ability against SARS-CoV-2 endoribonuclease (NSP15) and potentially bioactive molecules.

Throughout year 2023, researchers found and analysed a wide range of compounds, demonstrating the changing landscape of antiviral development. Prominent among the antiviral agents in 2023 are combinations of drugs such as bamlanivimab/etesevimab, casirivimab/imdevimab, and tixagevimab/cilgavimab have been actively researched and administered to enhance the efficacy of COVID-19 treatment, especially in high-risk patients. Remdesivir, Paxlovid (nirmatrelvir/ritonavir), and molnupiravir are well-known medicines still important in COVID-19 care. In addition to these proven drugs, the year saw the development of many new compounds having antiviral characteristics. Natural compounds such as cafestol, kahweol, and theaflavin 3,3′-digallate showed inhibitory potential in suppressing SARS-CoV-2 replication. Other potential possibilities were tested for antiviral efficacy, including dihydroergocristine, ergometrine, and ubidecarenone. The year also witnessed a concerted effort to better understand the immunomodulatory landscape of COVID-19. This effort included the development of several interleukin-6 inhibitors (such as tocilizumab and salirumab) and other antiviral drugs (such as Nakinra, baricitinib, and tofacitinib) in order to develop treatments that would reduce the severity of the disease.

As of 2024, the prevalence of clinical variations of concern (VoC) of SARS-CoV-2 in the U.S. renders them resistant to several neutralizing monoclonal antibodies (mAbs). The US FDA is now not allowing or is revoking several products, including REGEN-COV (casirivimab and imdevimab), Sotrovimab, Bamlanivimab and Etesevimab, Bebtelovimab, and Evusheld (tixagevimab/cilgavimab) as of the end of 2023. They cannot be used for pre-exposure prophylaxis to prevent or treat COVID-19 under the EUA. Meanwhile, several existing molecules have received FDA approval for COVID-19 treatment, including tocilizumab administered intravenously or subcutaneously, remdesivir as an intravenous therapy, baricitinib as an oral immune modulator, and Paxlovid (nirmatrelvir/ritonavir) as an oral antiviral treatment for adults and long-COVID patients. Tocilizumab is an intravenous or subcutaneous immune modulator for hospitalized children aged 2 to under 18 years. Vilobelimab is an intravenous infusion immune modulator approved for treating hospitalized adults, provided it is administered within 48 hours of initiating invasive mechanical ventilation (IMV) or extracorporeal membrane oxygenation (ECMO). Anakinra is an immune modulator approved for the treatment of COVID-19 in hospitalized adults with pneumonia who require supplemental oxygen, whether low- or high-flow and are at risk of developing severe respiratory failure. Molnupiravir is an oral antiviral that has received FDA authorization for emergency use in treating mild-to-moderate COVID-19 in individuals aged 18 and older at high risk for progression to severe COVID-19. Baricitinib is an oral immune modulator approved for emergency use in hospitalized children aged 2 to under 18 years who require supplemental oxygen, invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO) due to COVID-19. Ensitrelvir, a 3C-like protease inhibitor, when administered orally once a day for five days, dramatically decreased viral RNA levels by day 4 and showed a significantly quicker resolution of the five typical symptoms of the Omicron SARS-CoV2 (Yamato et al., 2024). Based on such evidences, Ensitrelvir received emergency approval in Japan in 2022. However, larger trials are required for further confirmation.