Structure and Inhibitor Development of Coronavirus Main Protease

NSP5

Shani Xiangyi Wang

Shanghai High School International Division, Shanghai, China

Keywords: SARS‑CoV‑2 Main Protease, Antiviral Inhibitors, Drug Design Strategies.

Abstract: The global health crisis triggered by COVID-19, a SARS-CoV-2 virus, has presented unparalleled challenges

on the global health system, resulting in nearly 770 million infections and more than 7 million fatalities by

the end of 2024. Despite significant advancements in vaccines and therapeutic interventions, the continuous

emergence of viral variants underscores the urgent need for effective antiviral therapies. The non-structural

protein (NSP) 5, a key enzyme for viral replication, has emerged as promising target for drug development

due to its critical role in viral polyprotein cleavage and high specificity, lacking homologs in human cells.

This article provides a methodical and comprehensive overview of NSP5 structural and functional

characteristics, along with recent development of NSP5 inhibitor discovery. Clinically approved inhibitors,

such as Paxlovid (Nirmatrelvir) and Xocova (Ensitrelvir), have demonstrated significant efficacy in reducing

severe disease outcomes and mortality rates. However, challenges such as viral mutations, drug resistance,

and pharmacokinetic limitations remain obstacles to long-term therapeutic success. The integration of

advanced computational strategies, including structure-based drug design (SBDD), ligand-based drug design

(LBDD), and artificial intelligence (AI)-driven approaches, has accelerated the discovery and optimization of

novel NSP5 inhibitors. Additionally, multi-target synergistic therapies and innovative drug design strategies

offer promising avenues to enhance antiviral efficacy and overcome resistance. This review also highlights

the importance of rigorous efficacy evaluations to ensure the safety, pharmacokinetic stability and clinical

viability of lead compounds. By consolidating existing knowledge and exploring future directions, this work

aims to contribute to the ongoing development of next-generation antiviral therapies, ultimately strengthening

global management of COVID-19 and preparedness for future coronavirus pandemics.

1 INTRODUCTION

The widespread COVID-19 pandemic has created

extraordinary damage to global society, causing

severe disruptions in several aspects, such as

healthcare, economic welfare, and social well-being

(Lew et al., 2020). The pandemic, triggered by the

rapidly spreading respiratory disease, emerged in late

2019 and quickly became the most profound global

health challenges in recent history (Lew et al., 2020).

By the end of 2024, nearly 770 million people around

the world have been infected by SARS-CoV-2, with

over 7 million reported deaths (WHO, 2024). The

mortality rate, although varying significantly across

regions and demographics, underscored the virus’s

severe impact, especially among high-risk

populations, such as the elderly and people with pre-

existing health issues (Greene et al., 2020; Nicola et

al., 2020). Despite remarkable advancements in

medical treatments and the development of effective

vaccines, the pandemic inflicted profound global

losses, exacerbating unemployment, intensifying

social distress, and disrupting healthcare systems and

economies on an unprecedented scale (Fahriani et al.,

2021). Moreover, the sustained evolution of SARS-

CoV-2 has made current antiviral treatments

insufficient, highlighting the urgent need for

innovative and effective therapies (Dhama et al.,

2023; Ren et al., 2022).

SARS-CoV-2, identified as a single-stranded,

positive-sense RNA virus, is a member of

the Coronaviridae family and

the Betacoronavirus genus. Its diameter is

approximately 80–120 nm. This virus features an

average of 24–40 spike proteins on its surface,

facilitating host cell entry. The RNA genome, about

30 kilobases (kb), encodes all the proteins necessary

for viral replication and assembly (V’kovski et al.,

Wang, S. X.

Structure and Inhibitor Development of Coronavirus Main Protease NSP5.

DOI: 10.5220/0014401000004933

Paper published under CC license (CC BY-NC-ND 4.0)

In Proceedings of the 1st International Conference on Biomedical Engineering and Food Science (BEFS 2025), pages 82-89

ISBN: 978-989-758-789-4

2020). SARS-CoV-2 replication occurs in four key

stages. First, the virus recognizes and binds to the host

cell receptor, angiotensin-converting enzyme 2

(ACE2), via the spike protein, enabling attachment to

the cell membrane. Next, the virus enters the cell via

endocytosis and releases its genomic RNA into the

cytoplasm, which is processed by the host's

ribosomes to generate sixteen non-structural proteins

(NSPs). Subsequently, replication-transcription

complexes (RTCs) are formed and participate in viral

genome replication and mRNA transcription. Finally,

newly synthesized structural proteins encapsulate the

replicated genomic RNA, and the fully

assembled virions are transported out of the host cell

through exocytosis (Chaudhary et al., 2021).

Multiple open reading frames (ORFs) exist in the

SARS-CoV-2 RNA genome. ORF1ab encodes the

NSPs essential for viral replication. One of the most

critical proteases in this process is NSP5, also referred

to as the main protease (Mpro). NSP5 is critical in the

cleavage of polyproteins, assisting the maturation of

viral proteins and eventually promoting viral

replication (Yoshimoto, 2021). Since NSP5 has no

homologous counterpart in mammalian hosts, it was

identified as a key candidate for antiviral drug

research due to this high specificity (Yadav et al.,

2021). Current strategies for designing NSP5

inhibitors include peptidomimetic covalent

inhibitors, non-covalent inhibitors, natural product-

derived inhibitors, and fragment-based screening

approaches (Yan & Gao, 2021).

Since 2019, several NSP5 inhibitors have been

developed, with some achieving regulatory approval

such as Pfizer's Paxlovid and Shionogi's Xocova.

Paxlovid (Nirmatrelvir) is a covalent inhibitor that

irreversibly binds to the catalytic Cys145 residue of

NSP5, thereby blocking its protease activity (Owen et

al., 2021). For clinical use, it is administered in

combination with ritonavir, which inhibits the

CYP3A4 metabolic enzyme (Pfizer, 2023). Xocova

(Ensitrelvir), a production of Shionogi & CO., LTD,

is a non-covalent inhibitor administered orally. It

replaces traditional peptidomimetic chains with a

rigid benzothiazole scaffold, enhancing metabolic

stability (Unoh et al., 2022). These inhibitors have

demonstrated significant efficacy in clinical trials,

substantially reducing severe disease outcomes and

mortality rates (Mukae et al., 2023; Yotsuyanagi et

al., 2024). Other NSP5 inhibitors under development

include Frontier Biotech (FB2001) (Shang et al.,

2022), Simcere Pharmaceutical (SIM0417) (Wang et

al., 2023), Enanta Pharmaceuticals (EDP-235)

(Rhodin et al., 2024), Rigel Pharmaceuticals

(RAY1216) (Wang et al., 2023), and Sorrento

Therapeutics (STI-1558) (Mao et al., 2024). These

investigational drugs aim to address the limitations of

current NSP5 inhibitors, such as toxicity, drug

resistance, and restricted patient populations, through

structural optimization and technological innovation,

offering improved options for next-generation

coronavirus treatments.

Considering the pivotal role of NSP5 in viral

replication and its potential for a drug target, this

article presents systematic overview of its structural

and functional characteristics, alongside recent

advancements in NSP5 inhibitor development. This

review also examines the structural biology of NSP5,

while addressing challenges such as viral mutations

that impact inhibitor efficacy. Furthermore, this

review synthesizes recent breakthroughs, including

novel inhibitors, new techniques (structure-based

drug design, AI-driven approaches) and multi-target

combination therapies. By consolidating existing

knowledge and recent findings, this work aims to

support ongoing efforts to establish effective antiviral

strategies against these coronaviruses, contributing to

the global management of COVID-19.

2 NSP5 STRUCTURE AND

FUNCTION

NSP5 is discovered as a cysteine protease, and its

molecular weight is close to 30 kDa. It is critical in

cleaving viral polyproteins, an essential process for

viral replication and maturation. Notably, the

sequence identity between SARS-CoV-2 NSP5 and

its SARS-CoV counterpart is 96%, although subtle

variations in the S1/S4 subsites influence inhibitor

binding efficiency and enzymatic activity. Its

catalytic activity is driven by a Cys145-His41 dyad,

and its substrate specificity is defined by the

recognition sequence Leu-Gln (Ser/Ala/Gly). Nsp5

functions as a homodimer, as revealed by X-ray

crystallography, with each monomer consisting of

three domains (I–III), including two N-terminal

domains that carry out the protease activity, and a C-

terminal domain composed of α-helices. The

substrate-binding pocket is located in a cleft between

domains II and III, enabling precise substrate

recognition and catalysis. The enzyme's sequence and

structure are highly conserved across all known

coronaviruses. The SARS-CoV-2 NSP5 can form a

homodimer, which recognizes substrates that are

about 10 amino acids long. However, it selectively

cleaves only at four specific positions within the

Structure and Inhibitor Development of Coronavirus Main Protease NSP5

polyprotein, exhibiting its tightly regulated enzymatic

function (Roe et al., 2021). Beyond its role in

processing viral proteins, NSP5 also contributes to

immune evasion by suppressing the host’s innate

immune response, partly by degrading host protein

factors (Rashid et al., 2022). Therefore, the main

protease NSP5 does not directly participate in

replication, it can be rephrased as NSP5 cleaves the

polyprotein to release non-structural proteins,

initiating genome replication. Due to this key

function, NSP5 is a critical drug target for developing

inhibitors (Jin et al., 2021).

3 CLINICALLY APPROVED

NSP5 INHIBITORS

3.1 Nirmatrelvir (Paxlovid,

PF-07321332)

Nirmatrelvir is a peptidomimetic covalent inhibitor,

developed by Pfizer (Owen et al., 2021). It mimics the

viral polyprotein substrate (e.g. Leu-Gln-Ser-Ala)

and contains an α-ketoamide warhead(-CO-NH-) that

can bind to the catalytic cysteine residue (Cys145) of

NSP5, irreversibly blocking its protease activity. This

compound is characterized by high activity and

selectivity. The IC₅₀ for the SARS-CoV-2 NSP5

inhibition was 19.3 nM, with an efficiency rate of

1,930 /Ms. It had no significant inhibitory effect on

human proteases, such as cathepsins. Nirmatrelvir has

cross-inhibitory activity against NSP5 in MERS-CoV

and SARS-CoV-1. In cellular assay, the IC₅₀ of this

compound for SARS-CoV-2 replication inhibition

was 74.5 nM. The activity against BA.1, BA.2

Omicron variants was maintained. In preclinical

animal infection models, oral administration of

Nirmatrelvir (300 mg/kg, twice daily) significantly

reduced lung viral loads (>90%) and alleviated

inflammatory damage. In the humanized ACE2

mouse model, survival rates increased to 100% with

Nirmatrelvir treatment, compared to 40% in the

control group, and the pathological damage in the

lungs was significantly alleviated (Owen et al., 2021).

Nirmatrelvir has low oral bioavailability and is

rapidly metabolized by cytochrome P450 3A4

(CYP3A4). Therefor combination with a CYP3A4

inhibitor (Ritonavir)is required to keep the plasma

concentration and therapeutic efficacy. Clinically,

Nirmatrelvir is co-packaged with Ritonavir, called

Paxlovid (Pfizer, 2023).

The EPIC-HR (NCT04960202) trial, non-

hospitalized adult patients receive Paxlovid BID for 5

days at 300 mg/100 mg. For the primary endpoint, the

relative risk reduction for Paxlovid group was 86%

(95%CI: 72%, 93%) compared to placebo group.

When administered within three days of symptom

onset, Paxlovid reduced hospitalization or death by

88%, and by 85% when administered within 5 days.

On day 5, the Paxlovid group showed a significantly

higher viral load reduction (10-fold difference) than

the placebo group. The virus clearance time is

shortened by about 2-3 days (Hammond et al., 2022).

In addition, its efficacy maintained against early

variants (e.g. Delta), though reduced against BA.2,

BA.5 Omicron subvariants due to viral evolution and

pre-existing immunity. Paxlovid remained effective

in reducing hospitalization risks by 52% during the

2022-2023 Omicron wave, according to data from

Hong Kong (Wong et al., 2022).

Paxlovid is generally well-tolerated, with common

adverse effect including dysgeusia, diarrhea, nausea,

and vomiting. Paxlovid treatment led to a 2.0%

discontinued rate, lower than the rate in the placebo

group (Hammond et al., 2022). Avoid drug-drug

interactions is the main shortage of Paxlovid.

Ritonavir’s inhibition of CYP3A4 leads to severe

interactions with medications metabolized by this

enzyme, such as statins, anticoagulants (e.g.

apixaban, rivaroxaban) and immunosuppressants

(e.g. tacrolimus). Co-administration with drugs that

strongly induce CYP3A4 (e.g. rifampin) may reduce

nirmatrelvir efficacy (Pfizer, 2023). In addition,

approximately 5-10% of patients experienced a

rebound in viral load (Paxlovid rebound) after

discontinuation, potentially linked to insufficient

treatment duration or immune response deficiencies

(Wang et al., 2022). Paxlovid is not advised for

critically ill patients in hospital (Pfizer, 2023).

3.2 Ensitrelvir (S-217622, Xocova)

Ensitrelvir is an orally non-covalent SARS-CoV-2

Mpro inhibitor developed by Shionogi. It reversibly

binds to the protease active site, potentially reducing

susceptibility to resistance mutations (e.g. E166V).

The structure of Ensitrelvir is precisely to achieve

high affinity for NSP5. The S1 pocket is occupied by

a 6-chloro-2-methyl-2H-indazole moiety to form

strong hydrophobic interactions. The 2,4,5-

trifluorobenzylic moiety occupies S2 pocket and

interacts with His41 (a catalytic residue) to enhance

the binding affinity. Ensitrelvir effectively inhibited

NSP5 enzymatic activity in SARS-CoV-2 with IC₅₀

at 24.1 nM. It also presented antiviral activity against

BEFS 2025 - International Conference on Biomedical Engineering and Food Science

HCoV-OC43, MERS-CoV and HCoV-229E with

at 0.074 μM, 1.4μM and 5.5 μM respectively.

The inhibitory effect on multiple Omicron variants,

including XBB.1.5 and BA.1/BA.2/BA.5, was well-

preserved (IC₅₀ ~20-100 nM). The oral bioavailability

of this compound is optimized through scaffold

optimization. A single dose regimen can maintain

effective plasma drug concentration, enabling once -

daily dosing. In a hamster infection model, Ensitrelvir

(30 mg/kg once a day) decreased the viral load in the

lungs by 3-log₁₀, associated with alleviated

pneumonia severity. Prophylactic administration (24

hours pre-exposure) completely blocked viral

replication. In hACE2 transgenic mice, Ensitrelvir

achieved a 100% survival rate, whereas 40% in the

control group, with undetectable viral loads three

days post- dosing (Unoh et al., 2022).

In the pivotal clinical trials, mild-to-moderate

COVID-19 patients were given Ensitrelvir (125 mg,

once daily) over 5 days. Symptom relief occurred 24

hours earlier in the Ensitrelvir group (median time:

167.9 hours vs. 192.2 hours) (Yotsuyanagi et al.,

2024). The time for fever relief in the treatment group

was shortened by approximately 30 hours. On the 4th

day, Ensitrelvir decreased the viral load by –1.4 to –

1.5 log10 copies/ mL, while that in the placebo group

decreased by 0.6-log₁₀. The rate of viral negativity

after Ensitrelvir treatment for 5 days was 68% (35%

in the placebo group) (Mukae et al., 2023). A

retrospective study in Japan in 2023 reported greater

viral titer change and lower total score of symptoms

after Ensitrelvir treatment during Omicron wave

(Mukae et al., 2023).

Ensitrelvir avoids the potential long-term toxicity

risks of covalent inhibitors. Due to its excellent

pharmacokinetics (PK), the single - drug oral regimen

significantly simplifies clinical use and broadens the

applicable population, such as patients with complex

co-medications. Currently, its indication is limited to

mild-to-moderate patients, and its efficacy in

hospitalized patients has not been verified.

4 DEVELOPMENT STRATEGIES

FOR NSP5 INHIBITORS

4.1 Computer-Aided Drug Design

4.1.1 Structure-based Drug Design

SBDD utilizes the three-dimensional structure of the

protease to identify and optimize lead compounds.

Cryo-electron microscopy (cryo-EM) and X-ray

crystallography were employed to reveal the high-

resolution structure of substrate-binding pockets and

active site. These structural data formed the

foundation for molecular docking simulations, which

predict the binding affinity and orientation of

potential inhibitors within the protease's active site

(Dai et al., 2020). Additionally, molecular dynamics

(MD) simulations allow for dynamic exploration,

revealing conformational changes and key

interactions between NSP5 and inhibitors over time

(Amorim et al., 2023). By integrating these

computational approaches, it is possible to design

compounds with enhanced binding efficiency,

specificity, and stability, thereby improving drug

development efficiency.

4.1.2 Ligand-Based Drug Design (LBDD)

LBDD complements SBDD by focusing on the

chemical properties of known inhibitors to identify

novel candidates. Machine learning (ML) algorithms

trained on datasets of experimentally validated NSP5

inhibitors can predict compounds with potential

antiviral activity (Mohamed et al., 2021). These

models analyze molecular descriptors, including

hydrophobicity, hydrogen bonding capacity, and

molecular weight to identify promising candidates.

The integration of SBDD and LBDD allows for a

comprehensive approach to inhibitor discovery,

facilitating the design of NSP5-targeted compounds

with improved potency and reduced off-target effects.

4.2 Lead Compound Optimization

The lead compounds optimization is a crucial step in

NSP5 inhibitor development, aiming to enhance

selectivity, bioavailability, and metabolic stability.

Structural modifications, such as the introduction of

cyclopropyl groups or the replacement of labile

functional groups, can improve the binding affinity

and pharmacokinetic properties. For example,

incorporating non-natural amino acids or

peptidomimetic scaffolds can significantly improve

oral bioavailability while maintaining strong

interactions with NSP5.

Chemical modifications also fulfill an essential

role in optimizing NSP5 inhibitors. The addition of

electron-withdrawing groups or the modulation of

steric hindrance can fine-tune binding interactions

between inhibitors and the protease, leading to

improved inhibitory potency. Additionally, prodrug

strategies, which convert inactive precursors into

Structure and Inhibitor Development of Coronavirus Main Protease NSP5

active inhibitors in vivo, can address challenges

related to poor absorption or rapid metabolism. These

optimization processes are guided by computational

predictions and validated through functional assays to

ensure that the optimized compounds retain high

antiviral activity while minimizing toxicity and

adverse effects.

4.3 Preclinical Efficacy Evaluation

The development of NSP5 inhibitors involves

rigorous in vitro and in vivo evaluations to determine

antiviral potency, pharmacokinetics, and safety. In

vitro studies are the initial step in evaluating the

antiviral potency and cytotoxicity of candidate

compounds. Cell-based assays using Vero E6 and

HEK293T cells are commonly employed to measure

the inhibition of viral replication and the compound's

effect on host cell viability. These experiments

provide essential preliminary data on the potency and

selectivity of inhibitors, guiding further structural

modifications and compound optimization.

Subsequently, in vivo efficacy studies are

conducted to evaluate the pharmacokinetics,

therapeutic efficacy, and potential toxicity of lead

compounds. Animal models, including mice and

hamsters, serve as preclinical platforms for

simulating virus infection and evaluating the potential

therapeutic potency of NSP5 inhibitors. Parameters

such as viral load reduction, immune response

modulation, and organ toxicity are monitored to

ensure that the selected compounds demonstrate both

safety and efficacy. These preclinical studies are

essential for selecting compounds with the highest

potential for clinical translation.

5 FUTURE PROSPECTS AND

CHALLENGES OF NSP5

INHIBITORS

5.1 Challenges in Research

The development of NSP5 inhibitors is confronted

with several notable challenges. A major concern is

the effect of viral mutations on inhibitor sensitivity.

As a key protease in viral replication, NSP5 is subject

to evolutionary changes that can modify its structural

binding sites, potentially reducing the efficiency of

current inhibitors. This mutation-driven resistance

not only limits the applicability of existing inhibitors

but also necessitates continuous optimization in drug

design strategies to address rapidly evolving viral

strains. Addressing these variations requires

structural monitoring of NSP5 mutants and the

development of inhibitors capable of maintaining

activity.

Another major issue in NSP5 inhibitor

development is the optimization of pharmacokinetics,

particularly absorption, distribution, metabolism, and

excretion (ADME) properties. Effective oral drugs

must be sufficient bioavailability and stability to

sustain therapeutic concentrations in vivo. However,

many candidate compounds that demonstrate

excellent activity in vitro fail in clinical trials due to

poor ADME characteristics. Therefore, improving

bioavailability through structural optimization and

formulation enhancements is a central focus of

current studies. Moreover, the assessment of safety

and long-term toxicity poses another major challenge

in the clinical translation of NSP5 inhibitors. While

NSP5 inhibitors effectively suppress viral replication,

they may also induce nonspecific toxicity in host

cells, particularly with prolonged administration.

Balancing antiviral efficacy with safety and

systematically evaluating potential risks through

toxicological studies are essential for advancing

NSP5 inhibitors toward clinical application.

5.2 Future Directions

To address the challenges in NSP5 inhibitor research,

future efforts should focus on several promising

directions. First, the discovery of novel covalent and

non-covalent inhibitors represents a critical strategy

for improving the therapeutic window. Covalent

inhibitors, which form irreversible bonds with NSP5,

can provide sustained suppression of viral replication

but require careful evaluation of potential toxicity due

to their permanent binding mechanism. Non-covalent

inhibitors, on the other hand, offer higher selectivity

but may be more susceptible to resistance caused by

viral mutations. Therefore, developing inhibitors that

combine high efficacy with safety is a key priority.

Second, multi-target synergistic therapy holds

significant potential for enhancing antiviral efficacy.

For example, combining NSP5 inhibitors with RNA-

dependent RNA polymerase (RdRp) inhibitors or

ACE2 receptor blockers could effectively disrupt

viral replication and infection at multiple stages,

thereby decreasing the risk of resistance and

improving therapeutic potency. The development of

such combination therapies requires a well-rounded

understanding of the synergistic mechanisms

between different targets and rigorous validation

BEFS 2025 - International Conference on Biomedical Engineering and Food Science

through clinical trials. Finally, the application of

artificial intelligence (AI) offers new opportunities to

accelerate drug discovery. AI-driven virtual

screening and molecular design can rapidly identify

compounds with potential antiviral activity and

optimize their pharmacokinetic properties. Moreover,

AI can predict the impact of viral mutations on

inhibitor sensitivity, guiding more effective drug

design.

In summary, the discovery of the next generation

of NSP5 inhibitor lies in the integration of novel

inhibitor development, multi-target synergistic

therapy, and AI-powered drug design. By addressing

the challenges and leveraging computational and

experimental techniques, the research on NSP5

inhibitors is poised to achieve groundbreaking

advancements, providing more effective solutions for

the development of broad-spectrum antiviral

treatment.

6 CONCLUSION

The worldwide coronavirus pandemic has

underscored the urgent request for effective antiviral

treatments to fight SARS-CoV-2 and its continuously

evolving variants. NSP5 has been proven to be a

particularly attractive therapeutic target, because of

its essential role in viral replication and the lack of

homologous proteins in human cells. This article has

provided a detailed insight of the structural and

functional characteristics of NSP5. The development

and clinical efficacy of approved NSP5 inhibitors,

such as Paxlovid (Nirmatrelvir) and Xocova

(Ensitrelvir), which have demonstrated significant

reductions in severe disease outcomes and mortality

rates have also been examined. These inhibitors,

along with others in development, represent

promising advancements in antiviral therapy, yet

challenges such as viral mutations, drug resistance,

and pharmacokinetic limitations remain.

The integration of advanced computational

strategies, including SBDD, LBDD, and AI-driven

approaches, has accelerated the discovery and

optimization of NSP5 inhibitors. These technologies

have enabled the identification of novel covalent and

non-covalent inhibitors, as well as the exploration of

multi-target combination therapies, which hold

promise for overcoming resistance and improving

therapeutic outcomes. Furthermore, rigorous

preclinical evaluations have been instrumental in

advancing lead compounds toward clinical

translation, ensuring both efficacy and safety profiles

are thoroughly validated.

Despite these achievements, several challenges

still exist. The persistent evolution of SARS-CoV-2

necessitates ongoing efforts to address mutation-

driven resistance and optimize drug design strategies.

Additionally, improving the pharmacokinetic

properties of NSP5 inhibitors, particularly enhancing

their oral bioavailability and metabolic stability,

remains a critical hurdle in drug development. The

development of next-generation inhibitors must also

prioritize safety, minimizing off-target effects and

long-term toxicity while maintaining high antiviral

efficacy.

Looking ahead, the future of NSP5 inhibitor

research lies in the integration of innovative

approaches, including the discovery of novel

inhibitors, the development of multi-target

synergistic therapies, and the application of AI

technologies. These efforts will not only enhance our

ability to combat SARS-CoV-2 but also contribute to

global preparedness for future coronavirus outbreaks.

By consolidating existing knowledge and leveraging

cutting-edge technologies, this review aims to support

ongoing research and development efforts, ultimately

contributing to the global antiviral strategies and

strengthening response to coronavirus and the

mitigation of future pandemics.

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Structure and Inhibitor Development of Coronavirus Main Protease NSP5