Small-molecule anti-COVID-19 drugs and a focus on China’s homegrown mindeudesivir (VV116)

Abstract

The coronavirus disease 2019 (COVID-19) pandemic has stimulated tremendous efforts to develop therapeutic agents that target severe acute respiratory syndrome coronavirus 2 to control viral infection. So far, a few small-molecule antiviral drugs, including nirmatrelvir–ritonavir (Paxlovid), remdesivir, and molnupiravir have been marketed for the treatment of COVID-19. Nirmatrelvir–ritonavir has been recommended by the World Health Organization as an early treatment for outpatients with mild-to-moderate COVID-19. However, the existing treatment options have limitations, and effective treatment strategies that are cost-effective and convenient for tackling COVID-19 are still needed. To date, four domestically developed oral anti-COVID-19 drugs have been granted conditional market approval in China. These drugs include azvudine, simnotrelvir–ritonavir (Xiannuoxin), leritrelvir, and mindeudesivir (VV116). Preclinical and clinical studies have explored the efficacy and tolerability of mindeudesivir and supported its early use in mild-to-moderate COVID-19 cases at high risk for progression. In this review, we discuss the most recent findings regarding the pharmacological mechanism and therapeutic effects focusing on mindeudesivir and other small-molecule antiviral agents for COVID-19. These findings will expand our understanding and highlight the potential widespread application of China’s homegrown anti-COVID-19 drugs.

Keywords

COVID-19 / antiviral drugs / mindeudesivir

1 Introduction

The coronavirus disease 2019 (COVID-19) pandemic has caused millions of deaths and continues to spread rapidly worldwide [1]. As of June 28, 2023, the World Health Organization (WHO) have reported over 767 million confirmed cases of COVID-19, which resulted in 6.9 million deaths. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has evolved into variants with increasing transmissibility and capability of evading human immunity, including Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2), and Omicron (e.g., BA.1) [2]. Omicron is currently the dominant and widely circulated variant worldwide. It rapidly triggered the fourth wave of the SARS-CoV-2 epidemic in southern African countries in 2022, which led to a drastic rise in infection numbers [3]. Infections with Omicron result in considerable immune evasion, and vaccine-induced neutralizing antibodies have been reported to have reduced effectiveness against Omicron variants [4,5]. Toward the end of 2022, China experienced a nationwide Omicron outbreak, with nearly 60%–80% of people in major cities affected by this major outbreak [6].

SARS-CoV-2 is a single-stranded RNA virus with a genome of about 30 kb [7]. The SARS-CoV-2 genome encodes 16 nonstructural proteins (NSP1 to NSP16), 4 structural proteins (spike, envelope, membrane, and nucleocapsid), and 9 accessory proteins. The life cycle of SARS-CoV-2 in human body includes viral entry, proteolytic processing, RNA synthesis, and assembly. The development of antiviral agents aims to block different stages of the life cycle [8]. Efforts to develop anti-COVID-19 drugs have led to the evaluation of various potential treatments in clinical trials, a few of which have reached the market, including remdesivir [9,10], nirmatrelvir–ritonavir (Paxlovid) [11], and molnupiravir [12]. However, existing treatment options have limitations, and effective, cost-effective, and convenient treatment strategies are still needed for COVID-19 patients.

Chinese homegrown anti-COVID-19 drugs have also played important roles in the treatment of COVID-19. Azvudine (FNC) was the first Chinese oral anti-COVID-19 drug [13]. In addition, mindeudesivir (VV116/JT001, also known as renmindevir) developed by a group of Chinese researchers has been reported to have potent activity against SARS-CoV-2 and was found to be noninferior to Paxlovid with respect to time of sustained recovery from COVID-19 [14,15]. Mindeudesivir was granted conditional approval to enter the Chinese market by the National Medical Products Administration (NMPA) on January 28, 2023. Another domestically developed oral anti-COVID-19 drug, namely, simnotrelvir–ritonavir (Xiannuoxin), was conditionally approved on the same day. Leritrelvir received conditional approval in March 2023. Here, we provide a comprehensive overview of small-molecule antiviral agents against SARS-CoV-2 and offer a detailed introduction to mindeudesivir.

2 Overview of small-molecule anti-SARS-CoV-2 drugs

To date, efforts in drug discovery to treat COVID-19 have led to the authorization of two classes of small-molecule antiviral drugs: inhibitors of NSP12 RNA-dependent RNA polymerase (RdRp) and inhibitors of NSP5 protease (M^pro) (Tab.1). The mechanism of action for small-molecule antiviral drugs is shown in Fig.1 [16]. However, the United States Food and Drug Administration (FDA) has approved only two antiviral agents to date: remdesivir and nirmatrelvir–ritonavir (Paxlovid). Paxlovid is the first oral antiviral pill approved by the FDA to treat COVID-19 in adults [17]. The FDA has issued an emergency use authorization (EUA) for molnupiravir for the treatment of patients with mild-to-moderate COVID-19 who are at risk of progression [18]. To date, the Chinese NMPA has granted conditional approval for four domestically developed small-molecule drugs: azvudine, simnotrelvir–ritonavir, mindeudesivir, and leritrelvir.

3 Small-molecule anti-COVID-19 drugs developed outside China

3.1 Remdesivir and molnupiravir (RdRp inhibitors)

The SARS-CoV-2 RdRp, as a highly conserved holoenzyme involved in viral RNA replication and transcription, is a promising drug target. Remdesivir (GS-5734) is an intravenous nucleotide prodrug that binds to NSP12 RdRp and inhibits viral replication [19]. It was initially synthesized in 2013 during the search for a potent nucleoside inhibitor of the respiratory syncytial virus [20]. To improve its intracellular delivery, remdesivir was synthesized as a monophosphoramidate prodrug of its parent nucleoside (GS-441524) [21]. After remdesivir diffuses across the cell membrane, it undergoes a series of metabolic conversions to generate the active metabolite remdesivir triphosphate. This metabolite competes with natural ATP substrates and is efficiently incorporated into nascent RNA chains, which causes delayed chain termination [19].

Soon after the COVID-19 outbreak, remdesivir’s potential as an anti-SARS-CoV-2 treatment was demonstrated in preclinical and clinical studies [22]. It became the first intravenously administered drug for the treatment of SARS-CoV-2 approved by the FDA. Clinical benefits of remdesivir have been indicated by randomized trials such as the Adaptive Covid-19 Treatment Trial (ACTT-1) (NCT04280705) and GS-US-540-9012 (PINETREE) (NCT04501952) [9,10]. Early treatment with remdesivir can reduce viral loads and the rates of hospitalization or all-cause death rate in outpatients with COVID-19. However, remdesivir is unsuitable for oral administration and lung-specific delivery due to its low oral bioavailability and low stability in human liver microsomes, which limits its widespread use during the pandemic. Notably, the antiviral efficacy of remdesivir has been questioned given that several randomized trials found that it had no significant effect or only a small effect on patient outcomes [23,24].

Molnupiravir is an oral prodrug that also targets RdRp and inhibits the replication of SARS-CoV-2 [25]. Its activity against SARS-CoV-2 in animal models was discovered in 2020 [26]. Clinical trials have also showed that molnupiravir can reduce the risk of hospitalization or death in non-hospitalized patients with COVID-19 [27]. However, due to concerns on the theoretical risk of human host cell mutation and its potential effects on SARS-CoV-2 mutations, the US Nation Institutes of Health (NIH) recommended using molnupiravir when Paxlovid and remdesivir are not available, not feasible to use, or not clinically appropriate [28].

3.2 Nirmatrelvir–ritonavir (M^pro inhibitors)

Nirmatrelvir is a SARS-CoV-2 main protease (M^pro) inhibitor, while ritonavir is a human liver cytochrome P450 3A4 (CYP3A4) inhibitor and has no activity against SARS-CoV-2 [29]. M^pro is involved in virion maturation and the production of nonstructural proteins, which are essential for assembling the viral replication transcription complex; consequently, M^pro inhibitor nirmatrelvir disrupts virion assembly, virion release, and subsequent new infections [30]. Given that nirmatrelvir is mainly metabolized by human liver CYP3A4, a strong CYP3A4 inhibitor like ritonavir can be co-administered to reduce CYP3A4-mediated metabolic clearance of nirmatrelvir, which increases the plasma concentration of nirmatrelvir [29]. Nirmatrelvir is a peptidomimetic that incorporates a nitrile warhead, which forms a bond with Cys145 of M^pro to achieve reversible inhibition [31].

In the Evaluation of Protease Inhibition for COVID-19 in High-Risk Patients (EPIC-HR) study (NCT04960202), early treatment with nirmatrelvir 300 mg plus ritonavir 100 mg (Paxlovid) twice daily for 5 days reduced COVID-19-related hospitalization or death from any cause among non-hospitalized adults at high risk of progressing to severe disease, with an 89.1% relative risk reduction compared with the placebo group [11]. The incidence of adverse events was similar in both groups. Based on the results of the EPIC-HR study, Paxlovid received full approval by the FDA in USA in May 2023 and has been authorized for emergency use by many countries, including conditional approval by the NMPA in February 2022. It is now recommended by the WHO guidelines as early treatment for outpatients with mild-to-moderate COVID-19 [32]. However, access to nirmatrelvir is limited worldwide, and its effectiveness depends on ritonavir, which has multiple drug–drug interactions that require specialized assessment before prescription. Furthermore, preliminary studies have indicated occasional COVID-19 rebound after Paxlovid treatment [33].

The chemical structure of nirmatrelvir is shown in Fig.2.

4 Small-molecule anti-COVID-19 drugs developed in China

4.1 Azvudine (RdRp inhibitor)

Azvudine (also known as FNC and RO-0622), which is a novel nucleoside-based broad-spectrum prodrug originally developed for human immunodeficiency virus (HIV) treatment, inhibits viral RdRp and restores expression of cytidine deaminase APOBEC3G (A3G) in HIV-1 patient-derived CD4⁺ T cells [34]. Azvudine has exhibited desirable pharmacokinetics, efficacy, and safety in phase I, II, and III clinical trials (GQ-FNC-2014-2, GQ-FNC-201, NCT04109183, and NCT04303598) for treating HIV infection [35,36]. Based on the pervious findings, researchers speculated that azvudine could be a drug candidate for COVID-19 treatment. They conducted a randomized, open-label, controlled clinical trial of azvudine tablets for the treatment of mild and common COVID-19 in China (ChiCTR2000029853) [37]. In this pilot study, 20 mild and common COVID-19 patients were randomly assigned to receive either azvudine or standard antiviral treatment. The mean time of the first nucleic acid negative conversion in the azvudine group was 2.60 days, which was much shorter than that in the control group (5.60 days). Four phase III multicenter, randomized, placebo-controlled clinical trials of azvudine were conducted in China, Russia, and Brazil. According to the results of the trial performed in Russia, azvudine significantly increased the proportion and shortened the median time for improvement in clinical conditions compared with placebo [38]. Specifically, 36.31% of the patients who received azvudine (n = 157) for 7 days showed improved clinical symptoms, while the proportion was 9.55% in those who received a placebo (n = 157) in the full analysis set (data obtained from the package insert of azvudine tablets manufactured by Henan Sincere Biotechnology Co., Ltd.). Furthermore, in the first real-world study evaluating the clinical efficacy of azvudine in hospitalized patients with COVID-19 and pre-existing conditions, azvudine treatment was found to be associated with significantly lower risks of composite disease progression compared with matched controls [39]. Based on the results of clinical trials and retrospective evidence, azvudine received conditional marketing authorization from the NMPA as China’s first self-developed oral small-molecule anti-COVID-19 drug. However, the usage and dosing of azvudine should be carefully evaluated in patients with impaired renal function. Drug–drug interactions are another potential concern. Notably, the clinical benefits of azvudine versus nirmatrelvir–ritonavir remain controversial, especially among hospitalized individuals, predominantly the elderly [40,41].

4.2 Simnotrelvir–ritonavir and leritrelvir (M^pro inhibitors)

Simnotrelvir–ritonavir (Xiannuoxin) is one of the early Chinese domestic small-molecule anti-SARS-CoV-2 drugs that received conditional market approval from the NMPA. Simnotrelvir (SIM0417) is a SARS-CoV-2 main protease (M^pro) inhibitor, while ritonavir serves as a human CYP3A4 inhibitor to enhance the systemic exposure of the former. Simnotrelvir has demonstrated broad-spectrum antiviral activity, acceptable pharmacokinetic properties, and safety profile in preclinical studies. Notably, it not only inhibits wild-type SARS-CoV-2 M^pro but also maintains inhibitory activity against the Delta and Omicron variants, with a half-maximal inhibitory concentration (IC50) < 100 nmol/L [42]. As reported in the phase Ib clinical study (NCT05369676), simnotrelvir plus ritonavir was generally well tolerated, and the recommended clinical dose was determined to be 750 mg of simnotrelvir plus 100 mg of ritonavir (Xiannuoxin) [42]. In 2022, a multicenter, randomized, double-blind phase II/III clinical study (NCT05506176) to evaluating the efficacy and safety of Xiannuoxin in symptomatic adult participants with mild-to-moderate COVID-19 was completed. According to a news release, Xiannuoxin displayed satisfactory safety profile and therapeutic effect. In comparison with the placebo, Xiannuoxin significantly shortened the time to sustained recovery of symptoms by 1.5 days. An even more significant reduction of 2.4 days was observed in a subgroup of participants at high risk for progression. With the imminent release of more detailed data, Xiannuoxin has the potential to become a promising and affordable therapeutic regimen for COVID-19 patients.

Leritrelvir (RAY1216) is a novel α-ketoamide-based M^pro inhibitor approved by the NMPA in 2023. Leritrelvir offers unique advantages compared with other M^pro inhibitors because it can be used as a single anti-COVID-19 agent without the need for co-administration with the CYP3A4 inhibitor ritonavir. This way may help avoid the restrictions and risks of drug combination [43]. Preclinical studies have indicated its antiviral activity against not only the wild-type but also the Alpha, Beta, Delta, and Omicron variants. In a randomized, double-blind, placebo-controlled clinical trial (NCT05620160) that included 1359 participants with mild-to-moderate COVID-19, leritrelvir demonstrated superior efficacy in shortening the time to sustained recovery of 11 symptoms and lowering viral load compared with the placebo. With the anticipated release of more detailed data, leritrelvir may provide additional treatment options for the elderly or patients accompanied with underlying diseases.

The chemical structures of simnotrelvir [44] and leritrelvir [45] are shown in Fig.2.

5 Mindeudesivir

5.1 Design and development of mindeudesivir

Considering the rapid spread of COVID-19, safe and effective oral antiviral agents are still needed. In such cases, oral GS-441524 derivatives (oral version of remdesivir) might prove to be more potent SARS-CoV-2 inhibitors effective against various variants [46].

In 2021, Xie and colleagues conducted in vitro screening for anti-SARS-CoV-2 activity using various nucleoside/nucleotide analogs in Vero E6 cells [13]. They discovered that only remdesivir and its parent nucleoside GS-441524 could remarkably inhibit the replication of SARS-CoV-2 at 5.0 μmol/L. GS-441524, with a half-maximal effective concentration (EC50) of 0.59 μmol/L, proved to be a more potent viral replication inhibitor than remdesivir in Vero E6 cells. They further modified GS-441524 by introducing different groups (halogen, hydroxyl, or cyano) at the 7-position of the pyrrolotriazine base. Among the six synthesized derivatives, only the fluoro-substituted nucleoside showed moderate anti-SARS-CoV-2 activity. They concluded that common structural modifications could lead to a significant decrease or loss of antiviral activity in this nucleoside.

As a result, they attempted to modify GS-441524 through deuteration, which might offer potential pharmacokinetic benefits. This modification led to the development of the 7-deuterated derivative X1, which demonstrated strong antiviral activity. However, it had poor water solubility and liposolubility, which resulted in low oral bioavailability in rats. To improve oral bioavailability, several ester prodrugs of X1 were designed. Pharmacokinetic studies in rats revealed that the tri-isobutyrate ester X6 exhibited good oral bioavailability. Given that X6 was difficult to be crystallized, an intensive salt screening of X6 was performed. Among all the solids obtained, the hydrobromide salt VV116 emerged as the most qualified candidate. This salt had remarkably improved oral bioavailability [14]. The chemical structure of the GS-441524 derivative mindeudesivir (VV116) is shown in Fig.3 [47].

In terms of its antiviral molecular mechanism, mindeudesivir functions by targeting the highly conserved viral RNA dependent RNA polymerase through its nucleoside triphosphate form. This action blocks SARS-CoV-2 replication by evading the “proofreading” of viral RNA sequences [14]. Specifically, the postulated activation pathway of mindeudesivir involves four steps: oral absorption, hydrolysis of the ester group, phosphorylation, and incorporation into the growing SARS-CoV-2 RNA strand.

5.2 Preclinical studies of mindeudesivir

Preclinical pharmacokinetic, metabolism, and safety studies on mindeudesivir have been conducted in Sprague Dawley (SD) rats, mice, and Beagle dogs. First, for preclinical safety evaluation, mindeudesivir demonstrated good safety in rats and Beagle dogs, and the maximal tolerated single doses of mindeudesivir were at least 2.0 g/kg and 1.0 g/kg, respectively [14]. Considering the therapeutic window, no observed adverse effect levels (NOAELs) for 14 days repeated dose toxicity studies were 200 mg/kg in rats and 30 mg/kg in dogs. Besides, oral bioavailability of mindeudesivir reached up to 80% in rats, 90% in dogs [14], and 110.2% in ICR mice [46].

Importantly, the anti-SARS-CoV-2 efficacy of orally-administrated mindeudesivir was evaluated in hACE2-transduced mice, with another oral nucleoside analog molnupiravir (EIDD-2801) as the positive control [14]. A dose-dependent efficacy in reducing both the viral RNA copies and infectious virus titers in the lung tissues was found in mindeudesivir group, where more prominent efficacy presented at day 5 post infection (p.i.). The virus titers decreased below the detection limit with high dose (100 mg/kg) of mindeudesivir at day 2 p.i., and medium dose (50 mg/kg) at day 5 p.i. [14]. Histopathologic examination also proved that 100 mg/kg of mindeudesivir improved the degree and decreased the area of interstitial inflammatory lesions which occurred in the vehicle-treated control [14].

It is noteworthy that the key metabolite X1 of mindeudesivir was well distributed in targeted organs including intestine, lung, kidney, liver, heart, and brain in SD rats (30 mg/kg) as well as Balb/c mice (100 mg/kg). However, for remdesivir, concentration of its metabolite ¹⁴C-GS-5734 in the liver was about 23 times (1 h) and 37 times (4 h) of that in lungs in SD rats [48]. It suggested that oral mindeudesivir administration managed to circumvent the high liver-targeting issues which presented in remdesivir.

The above preclinical results indicate that mindeudesivir is a safe and effective oral nucleoside drug candidate against SARS-CoV-2.

5.3 Clinical studies of mindeudesivir

5.3.1 Phase I clinical studies

Considering the promising therapeutic usage of mindeudesivir against SARS-CoV-2 in preclinical studies, three phase I clinical studies in healthy individuals have been completed in China (NCT05227768, NCT05201690, NCT05221138) [49]. These studies aimed to evaluate the safety, tolerability, and pharmacokinetics of single and multiple ascending oral doses of mindeudesivir, as well as the effect of food on the pharmacokinetics and safety of mindeudesivir.

In the single ascending-dose study (Study I), 38 eligible participants were randomized into five dose groups (25, 200, 400, 800, and 1200 mg). The first group included 6 subjects, while the other groups had 8 subjects each. Participants received either the drug or placebo at a 3:1 ratio and were monitored for 48 h. The metabolite of mindeudesivir after oral administration, known as 116-N1, quickly reached its peak plasma drug concentration, with a median time to peak plasma concentration (T_max) of 1.00–2.50 h. It was eliminated with a median elimination half-life (t_1/2) of 4.80–6.95 h, which supported a twice-daily dosing regimen. Regarding the main pharmacokinetic parameters, the area under the curve (AUC) and maximum plasma concentration (C_max) increased in an approximately dose-proportional manner in the dose range of 25–800 mg, where drug absorption saturation was likely achieved. In the multiple ascending-dose study (Study II), 36 participants were enrolled in three dose groups (200, 400, and 600 mg). Participants received the drug or a placebo twice a day (12 h apart) for 5.5 days. The dosing regimen of 200 mg twice daily (BID) and higher doses consistently maintained effective antiviral concentrations and showed slight accumulation. In the food effect study (Study III), 12 participants were divided into three groups. Each subject took a single oral dose of 400 mg mindeudesivir either after overnight fasting or consumption of a standard meal or a high-fat meal, with a 3-day washout period in between. As indicated, the fed condition prolonged the time to peak compared with the fasting condition. However, C_max or AUC was not significantly affected by a regular meal.

In terms of safety and tolerability, the incidence of adverse events in the mindeudesivir group was lower or comparable to the placebo group. All adverse events were classified as CTCAE Grade I or II and resolved without any treatment. No obvious toxicity was observed in the eyes, thyroid, and gonads, which were identified as target organs for toxicity in preclinical animal toxicology studies. No participants withdrew from the study, and no serious adverse events occurred.

Evidence above in healthy Chinese participants showed that mindeudesivir exhibited satisfactory safety and tolerability and supported the further clinical investigation of mindeudesivir in patients with COVID-19.

5.3.2 Phase II/III clinical studies

Despite the promising data from the relatively small-scale studies mentioned above, the effect of mindeudesivir on the recovery and symptom resolution of COVID-19 patients from a large-scale population remained undetermined, particularly when compared with nirmatrelvir–ritonavir (Paxlovid), which is the anti-COVID-19 drug recommended by the WHO guideline [40]. In 2022, Ruijin Hospital Affiliated with Shanghai Jiao Tong University School of Medicine launched a large phase III clinical trial [15] during the national Omicron outbreak in China. During the study, when nearly 90% of the Chinese population had received standard-course vaccination [50], multi-center, randomized controlled trial was conducted. Symptomatic mild-to-moderate COVID-19 patients at high risk for disease progression were randomly assigned in a 1:1 ratio to receive either oral mindeudesivir (n = 384) or nirmatrelvir–ritonavir (n = 387) for 5 days. The trial demonstrated that mindeudesivir was noninferior to nirmatrelvir–ritonavir in reducing the time to sustained clinical recovery (4.0 vs. 5.0 days, median). Mindeudesivir also exhibited similar efficacy in terms of sustained symptom resolution and time to the first negative SARS-CoV-2 test. Notably, the incidence of adverse events was lower in the mindeudesivir group than in the nirmatrelvir–ritonavir group (67.4% vs. 77.3%) by day 28. Importantly, both groups experienced neither dead cases nor progression to severe COVID-19. This phase III study further confirmed the efficacy and tolerability of mindeudesivir and supported its early use in mild-to-moderate COVID-19 cases at high risk of progression. Notably, the authorization of Paxlovid was based on its efficacy in unvaccinated patients [11], but the data from this study fill a gap by supporting the benefits of mindeudesivir in patients who have received standard- or booster-course vaccinations, which accounted for 75.7% of the study population. Another multi-center, double-blind, randomized, placebo-controlled trial (NCT05582629) evaluating the efficacy and safety of mindeudesivir among mild-to-moderate COVID-19 patients has completed. The interim analysis revealed that, among 1277 randomized and treated participants, the mindeudesivir group experienced a substantially shorter time from the first administration to sustained clinical symptom resolution than the placebo group, with a median time difference of 2 days. Based on the findings from these clinical trials, mindeudesivir received conditional approval from the NMPA on January 28, 2023.

Mindeudesivir has also been investigated in other clinical trials (Tab.2), and the findings of some of these trials are expected to be released soon.

5.3.3 Non-randomized clinical study of mindeudesivir

A non-randomized clinical trial was conducted in hospitalized Chinese participants who were newly infected with the Omicron variant, which was the predominant variant in 2022 [51]. Most patients had mild cases, with moderate cases accounting for approximately 5% of the total participants. Among them, 60 patients were enrolled in the mindeudesivir group, where they received 300 mg of the drug every 12 h for 5 days. A total of 76 patients declined mindeudesivir and served as the control group. The mindeudesivir group exhibited a shorter viral shedding time (9.92 vs. 11.13 days) than the control group. A significant difference was found between the mindeudesivir group and the control group, particularly in the subgroup with the first positive test ≤ 5 days (8.56 vs. 11.13 days), as opposed to those with a first positive test result > 5 days after infection (11.46 vs. 11.13 days). Furthermore, symptomatic patients in the mindeudesivir group had a significantly shorter viral shedding time than those in the control group (10.00 vs. 12.25 days). A total of 9 (15.0%) adverse events (7 of which were mild liver function abnormalities) occurred in the mindeudesivir group, with no serious adverse events reported. This non-randomized intervention study implies that mindeudesivir could accelerate the viral shedding by 2–3 days when administered early in the course of the infection (≤ 5 days).

6 Future of mindeudesivir and other small-molecule anti-COVID-19 drugs

Mindeudesivir, as a prodrug of parent compound remdesivir, has overcome major deficiencies, including the need for injection, liver-targeting delivery, and potential safety concerns. In comparison with other oral drugs, mindeudesivir was noninferior to Paxlovid in terms of clinical efficacy. Moreover, it resulted in fewer adverse events and avoided significant drug–drug interactions. Consistent results from a series of studies have provided more robust evidence for the clinical use of mindeudesivir. Notably, mindeudesivir showed no mutagenicity, which addressed a constant concern for molnupiravir [14,52]. According to the results from preclinical and clinical studies, as well as its limited drug–drug interactions, considerable bioavailability, satisfactory pharmacokinetics, and safety profile, mindeudesivir has demonstrated strong support as a promising treatment for COVID-19. Its antiviral efficacy in reducing viral loads and mitigating lung injury (even against different SARS-Cov-2 variants), as well as its large-scale manufacturing capabilities, further highlight its potential.

However, current studies on mindeudesivir, as well as other small-molecule anti-COVID-19 drugs domestically developed in China, still have limitations. These studies lack evidence from internationally multi-center trials involving heterogeneous populations. Furthermore, mindeudesivir is conditionally indicated for mild-to-moderate COVID-19 patients, and its therapeutic effect on severe cases and patients with multiple complications remains unclear. Moreover, data on SARS-CoV-2 viral rebound following mindeudesivir treatment are lacking, which is a nonnegligible concern after nirmatrelvir–ritonavir and molnupiravir treatment [53].

During the Omicron-predominant era, large-scale real-world studies are warranted to explore the effectiveness of domestic anti-COVID-19 drug treatments among patients with different subvariants. A recent retrospective cohort study has suggested the effectiveness of nirmatrelvir–ritonavir for non-hospitalized patients during the Omicron period, including the BA.4 and BA.5 subvariants [54]. Meanwhile, optimized drug combination therapies of mindeudesivir are worth exploring, which may enhance synergistic efficacy. Although the emergency phase of the pandemic has temporarily subsided, the potential threats should never be ignored. Future studies could also be designed to examine the effect of mindeudesivir treatment on long COVID, including chronic fatigue syndrome, respiratory symptoms, and cognitive dysfunction that last for over 2 or 3 months following SARS-CoV-2 infection [55,56]. Currently, the mechanism of long COVID remains unclear, and viable treatment and prevention methods are yet to be identified. Given that SARS-CoV-2 is expected to be an endemic seasonal respiratory virus that will lead to millions of infections for the foreseeable future [57], potent treatment options like mindeudesivir deserve further investigation and optimization. Furthermore, considering the pan-coronavirus potential [58–60] and the demonstrated anti-respiratory syncytial virus effect [47] of NSP12 inhibitors in preclinical studies, the evaluation and development of mindeudesivir against multiple virus infection merit further exploration.

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