INTRODUCTION:

The new coronavirus SARS-CoV-2, which triggered the COVID-19 pandemic, has unleashed an unparalleled global health catastrophe that calls for quick and creative remedies.. Among the various strategies for combating the virus, inhibiting the main protease enzyme (M^pro) has emerged as a promising therapeutic approach. M^pro plays a pivotal role in the viral life cycle by cleaving polyproteins, enabling viral replication, and facilitating the production of essential viral proteins. As such, it presents an attractive target for antiviral drug development^1-2.

In the quest for effective COVID-19 management, this study embarks on a journey to explore the potential of bioactive metabolites as inhibitors of M^pro. Bioactive metabolites, found in diverse natural sources like plants, fungi, and marine organisms, have long been recognized for their multifaceted pharmacological properties. They possess the ability to interfere with crucial biological processes, making them candidates for disrupting viral replication³.

This review endeavour aims to elucidate the inhibitory effects of bioactive metabolites on M^pro, shedding light on the mechanisms of action and the binding interactions that underpin their potential as therapeutic agents. Moreover, it explores the prospects of developing bioactive metabolite-based drugs for COVID-19 treatment, with a focus on safety and efficacy. By delving into the uncharted territory of harnessing bioactive metabolites to target M^pro, this review holds promise for advancing our understanding of COVID-19 management and contributing to the development of innovative and effective treatments in the ongoing battle against the virus⁴.

2. Bioactive Metabolites as Potential Inhibitors of M^PRO:

In this section, we will delve into the concept of bioactive metabolites and their promising role in drug discovery, with a particular focus on their significance as potential inhibitors of the Main Protease (M^pro) enzyme in the context of COVID-19 management.

2.1 Concept of Bioactive Metabolites:

Bioactive metabolites are chemical compounds produced by living organisms as part of their metabolic processes. These metabolites are often characterized by their ability to interact with biological systems, exhibiting various physiological effects. They can be found in a wide range of organisms, including plants, microorganisms, marine organisms, and fungi. Bioactive metabolites have been a valuable resource for drug discovery and development due to their diverse and often unique chemical structures⁵.

2.2 The Potential of Bioactive Metabolites in Drug Discovery:

Bioactive metabolites have played a crucial role in the history of pharmaceuticals and continue to hold great potential in the field of drug discovery for several reasons⁶:

2.2.1 Chemical Diversity:

Bioactive metabolites are known for their structural diversity, making them a rich source of novel compounds with unique pharmacological properties.

2.2.2 Biological Activity:

These metabolites have evolved within organisms to serve specific functions, often involving interactions with biological targets. This inherent biological activity makes them attractive candidates for drug development.

2.2.3 Adaptation to Environmental Conditions:

Organisms produce bioactive metabolites as part of their defence mechanisms, environmental adaptations, or signalling processes. This can result in compounds with potential therapeutic effects.

2.2.4 Low Toxicity:

Many bioactive metabolites have evolved to interact with biological systems with minimal toxicity, making them safer candidates for drug development.

2.3 Natural Products and Secondary Metabolites as Sources of M^pro Inhibitors:

In the context of COVID-19 management, the Main Protease (M^pro) of SARS-CoV-2 is a critical target for drug development, as it plays a central role in viral replication. Bioactive metabolites, particularly those derived from natural products and secondary metabolites, hold promise as inhibitors of M^pro for the following reasons^7-8:

2.3.1 Historical Success:

Natural products have a long history of being used as sources of pharmaceuticals. Compounds like penicillin, derived from fungi, have revolutionized medicine.

2.3.2 Biosynthetic Potential:

Secondary metabolites, often produced by organisms in response to environmental stress, can include bioactive compounds with antiviral properties.

2.3.3 Diverse Sources:

The natural world is teeming with diverse organisms, each potentially harbouring unique bioactive metabolites that could serve as M^pro inhibitors.

2.3.4 Reduced Resistance:

Natural product-derived compounds may have a lower likelihood of promoting viral resistance due to their complex structures and multiple modes of action.

3. GENERAL COVID CONSTRUCTION:

In figure 1, coronaviruses have the most extensive, non-segmented, and favourable RNA genomes of any RNA virus. The corona-RNA virus's genome is encased in a helical capsid made up of nucleocapsid (N) protein. The RNA-nucleocapsid key is surrounded by a bi-lamination of lipid comprised of membrane (M) protein, spike (S) protein, and envelope (E) protein.

Figure 1: General Covid Construction

A single most important transmembrane zone connects the S protein to the cover, which has a few intracellular wings. The large ectodomain of the S protein spreads outward, giving the virus a crown-like appearance (crown is the meaning of corona in Latin). The ectodomain of the S protein facilitates viral entry by combining these three S1 subunit tops for receptor binding and a trimeric of S2 subunit shoots for membrane fusion^9-10.

4. Main Protease (Mpro) Structure and Function:

In this section, we will provide an overview of the structure and function of the SARS-CoV-2 Main Protease (M^pro) and explain its significance as a target for antiviral drug development.

4.1. Structure of SARS-CoV-2 M^pro:

The Main Protease, also known as 3CL protease, plays a pivotal role in the replication of SARS-CoV-2, the virus responsible for COVID-19. It is an essential enzyme for the virus's life cycle. The structure of SARS-CoV-2 M^pro is well-defined and consists of two domains¹¹:

4.1.1 N-terminal Domain:

This domain functions as a chymotrypsin-like serine protease. It contains a catalytic dyad consisting of Cysteine 145 and Histidine 41, which is crucial for its enzymatic activity.

4.1.2 C-terminal Domain:

This domain is involved in substrate recognition and binding. It acts as a substrate-specificity domain that helps Mpro recognize and cleave viral polyproteins.

The SARS-CoV-2 M^pro's structural organization is highly conserved among coronaviruses, making it an attractive target for antiviral drug development.

4.2 Function of SARS-CoV-2 Mpro:

The primary function of the Main Protease (M^pro) in SARS-CoV-2 is to cleave large viral polyproteins into individual functional proteins required for viral replication. This proteolytic processing is essential for the assembly of new viral particles. M^pro specifically recognizes and cleaves viral polyproteins at specific sites containing a conserved recognition sequence.

The viral polyproteins processed by M^pro include those involved in RNA replication and transcription, as well as structural proteins crucial for the formation of new virus particles. Inhibiting the enzymatic activity of M^pro disrupts this essential viral replication process and can effectively impede the spread of the virus within the host ¹².

4.3 Significance of M^pro as a Target for Antiviral Drug Development:

The significance of M^pro as a target for antiviral drug development in the context of COVID-19 management is multifaceted ^{7, 13}:

4.3.1 Central Role in Viral Replication: M^pro plays a central role in the replication of SARS-CoV-2 by cleaving viral polyproteins into functional components required for viral assembly and replication. Targeting M^pro can disrupt this process, hindering viral replication.

4.3.2 Conserved Structural Features: The structural features of M^pro are relatively conserved among coronaviruses, making it an attractive target not only for SARS-CoV-2 but also for potential future coronaviruses.

4.3.3 Limited Host Analogues: M^pro exhibits limited structural similarity to human proteases, reducing the risk of off-target effects on host proteins.

4.3.4 Potential for Drug Development: Inhibitors of M^pro can be developed as antiviral drugs, and there is a growing body of research exploring various compounds for their M^pro inhibitory activity.

5. Bioactive Metabolites with M^pro Inhibition Potential:

In this section, we will review specific bioactive metabolites derived from various sources, including plants, fungi, marine organisms, and more, that have demonstrated M^pro inhibitory activity.

5.1 Plant-Derived Bioactive Metabolites:

Several plant-derived bioactive metabolites have shown potential as M^pro inhibitors in the context of COVID-19 management.

Examples include:

5.1.1 Quercetin: This flavonoid found in various fruits and vegetables has demonstrated M^pro inhibition. It is believed to interact with the catalytic site of M^{pro 14}.

5.1.2 Epigallocatechin gallate (EGCG): A polyphenol abundant in green tea, EGCG has shown M^pro inhibitory activity. It may disrupt M^pro's enzymatic function ¹⁵.

5.2 Fungal Metabolites:

Fungi have also been a source of bioactive metabolites with M^pro inhibitory potential. For instance:

5.2.1 Lopinavir and Ritonavir: While these are synthetic protease inhibitors, they have structural similarities to fungal metabolites, making them effective against Mpro by blocking its active site ¹⁶.

5.3 Marine-Derived Compounds:

Marine organisms have yielded several bioactive metabolites with M^pro inhibitory properties:

Nucleoside Analogues: Some marine-derived nucleoside analogues have demonstrated M^pro inhibition. They can interfere with viral RNA synthesis ⁷.

5.3.1 Sulphated Polysaccharides: Compounds like heparin sulphate from marine sources have shown potential in inhibiting M^pro by binding to its active site.

5.4 Mechanisms of Action:

In figure no.5, protease inhibitors make alteration or inactivate the arrangements of protease concerned in the proteolytic events connected with diseases like AIDS, hepatitis, cancer, cirrhosis and thrombosis ¹⁷. The protease enzyme found in various types of organisms and major role is to conduct cellular functions by catalysing the proteolytic cleavage of a specific coding sequences. It also processes strand of precursor of viral proteins up to the maturation of virus like viral caspid proteins, replication and any other non-structural proteins. So, this method target protease enzyme of virus and inhibit it by changing their configuration and inactivate the virus by the help of plant extracts¹⁸.

Figure no. 5. Mechanism of Main Protease (M^pro) Enzyme

The mechanisms of action of these bioactive metabolites as M^pro inhibitors can vary, but they generally involve the following^7,12,13,14:

5.4.1 Binding to the Active Site: Many bioactive metabolites interact with the catalytic site of M^pro, preventing it from cleaving viral polyproteins.

5.4.2 Disruption of Enzymatic Function: Some compounds, such as quercetin and EGCG, disrupt the enzymatic activity of M^pro by blocking its catalytic dyad.

5.4.3 Allosteric Inhibition: In some cases, bioactive metabolites may inhibit M^pro by binding to allosteric sites, causing conformational changes that hinder its activity.

5.4.4 Substrate Mimicry: Compounds like lopinavir and ritonavir mimic substrates of M^pro, leading to its inhibition.

In table 1, Several medicinal herbs are considered to target the pathogenic Mpro or 3CLpro enzyme, which is necessary for coronavirus growth.

Table 1: Potential of Traditional Plants in Main Protease (M^pro) Enzyme Inhibition

S. No.	Botanical Name and Family	Common Name	Active Principles/ Plant metabolites	Inferences
1.	Anethum graveolens and Apiaceae	Dill and other flavonoid plants	Kaempferol, luteolin‐7‐glucoside, quercetin, demethoxycurcumin, apigenin‐7‐glucoside, naringenin, curcumin, catechin, oleuropein, epigallocatechin‐gallate, gingerol, zingerol, and allicin	Several herbal substances that are strong COVID-19 M^pro inhibitors were reviewed based on research studies ¹⁹
2.	Citrus limon and Rutaceae	Lemon and other citrus species	Acacetin, cardamonin, auraptene, daidzein, glabridin, epicatechin, herbacetin, taxifolin hydrate, and isoxanthohumol	Suppressed viral replication of CoV M^pro and had antiviral action ²⁰
3.	Citrus sinesis and Rutaceae, Piper nigrum and Piperaceae	Orange, black pepper, citrus fruits	Hesperidin, cannabinoids, pectolinarin, diosmin, rhoifolin, apiin, epigallocatechin gallate, diacetyl curcumin, and other secondary metabolites as beta,beta′‐(4‐Methoxy‐1,3‐phenylene)bis(2′‐hydroxy‐4′,6′‐dimethoxyacrylophenone and Additionally, (E)‐1‐(2‐hydroxy‐4‐methoxyphenyl)‐3‐[3‐[(E)‐3‐(2‐hydroxy‐4‐methoxyphenyl)‐3‐oxoprop‐1‐enyl]phenyl]Traditional remedies have bioactive inhibitors that are prop-2-en-1-one against main protease of SARSCoV-2	Bioactive inhibit towards SARSCoV2 major protease are from traditional medicines ^21,²²
4.	Psorothamnus arborescens and Fabaceae or Leguminosae	Legumes	Isoflavone	Inhibit the viral M^{pro 23}
5.	Phyllanthus emblica and Phyllanthaceae	Amla	(2S)-Eriodictyol 7-O-(6″-O-galloyl)-beta-d-glucopyranoside	Inhibit the viral M^{pro 23}
6.	Phaseolus vulgaris and Fabaceae or Leguminosae	Legumes	3,5,7,3′,4′,5′-hexahydroxy flavanone-3-O-beta-d-glucopyranoside	Inhibit the viral M^{pro 23}
7.	Hyptis atrorubens and Lamiaceae	Hyptis	Methyl rosmarinate	Inhibit the viral M^{pro 23}
8.	Myrica cerifera and Myricaceae	Southern wax myrle and bayberry	Myricitrin	Inhibit the viral M^{pro 23}
9.	Camellia sinensis and Theaceae	Tea	Myricetin 3-O-beta-d-glucopyranoside	Inhibit the viral M^{pro 23}
10.	Amaranthus tricolor and Amaranthaceae	Edible Amarnath	Amaranthin	Inhibit the viral M^{pro 23}
11.	Glycyrrhiza uralensis and Fabaceae or Leguminosae	Chinese liquorice	Licoleafol	Inhibit the viral M^{pro 23}
12.	Azadirachta indica and Meliaceae	Neem	Nimbidin, meliacinanhydride, nimocinol, nimbinene, nimbolide, nimbandiol, isomeldenin, and zafaral	COVID-19 M^pro might be inhibited by leaves of Azadirachta indica ²⁴
13.	Ocimum sanctum and Lamiaceae	Mints	Chlorogenic acid and luteolin-7-O-glucuronide	might directly attach to Cys145 of CoV's Mpro, preventing viral enzymes from working ²⁵
14.	Tinospora cordifolia and Menispermaceae	Guduchi, Moonseed, Giloy	Berberine, tinosponone, cardiofolioside B, xanosporic acid, and tembetarine, among other bioactive constituents	Shown to have a substantial docking rating. Among these drugs, tinosponone is a blocker of coronavirus M^pro, and molecular dynamics simulations validated the complex's longevity ²⁶
15.	Andrographis paniculate and their family is Acanthaceae	Green chiretta	Contains Andrographolide	Docking research has revealed that andrographolide inhibits M^proof CoV ²⁷
16.	Curcuma longa and Zingiberaceae	Turmeric, haldi	(4Z,6E)-1,5-dihydroxy-1,7-bis(4-hydroxyphenyl)hepta-4,6-dien-3-one and (1E,6E)-1,2,6,7-tetrahydroxy-1,7-bis (4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-dione)	Docking research was used to screen 267 compounds in Curcuma longa and discovered to be chief agents. When compared to lopinavir and shikonin, both drugs have the lowest binding score against M^pro protein and then also connect to the enzymatic portion of the M^pro protein more successfully ²⁸
17.	Camellia sinensis and Theaceae and Withania somnifera and Solanaceae, or nightshades	Winter cherry and Green tea	Polyphenols and withanolides	M^pro antagonists of CoV are accepted as true ^29,³⁰
18.	Houttuynia cordata and Saururaceae	Chameleon Plant, Heartleaf, Fishwort	Essential oil and alkaloids	In India, it has long been used to cure temperature and cold M^pro ³¹
19.	Isatis indigotica and Brassicaceae	Woad (Mustard family)	Phytomolecules of indigo, sinigrin, and β-sitosterol	Used in China traditionally for cure of viral diseases, e.g., influenza, hepatitis, and encephalitis and also inhibit the M^pro enzyme to stop the viral replication ^32,³³
20.	Torreya nucifera and Taxaceae	Japanese nutmeg-yew or Japanese torreya	Myricetin, amentoflavone and scutellarein	possess inhibition of M^pro ³⁴
21.	Chamaecyparis obtusa and Juniperus formosana and Cupressaceae	Hinoki false cypress, prickly cypress and Formosan juniper	Savinin, betulonic acid and ferruginol and forskolin	Demonstrated as very active competitive inhibition of M^pro ³⁵
22.	Tripterygium regelii and Celastraceae	Sprague and Takeda	4 quinone-methide triterpenes	M^pro inhibitory potentiality ³⁶
23.	Rhizome of Cibotium barometz (Dicksoniaceae), Dioscorea batatas (Dioscoreaceae), stem of Cassia tora (Fabaceae, Leguminosae), seeds of Gentiana scabra (Gentianaceae), and leaves of Taxillus chinensis (Loranthaceae)	Chinese yam, Golden Chicken Fern, Long dan cao, taxillus, sickle senna	Adena It was believed that essential oils, polyphenols, flavonoids, and alkaloidal phytomolecules	quite effective at inhibiting CoV Mpro.³⁷
24.	Chinese plants reserving alkaloids, phenols and flavonoids	Chinese plants reserving alkaloids, phenols and flavonoids	Coumaroyltyramine, quercetin, N-cis-feruloyltyramine, desmethoxyreserpine, kaempferol, betulinic acid, cryptotanshinone, dihomo-γ-linolenic acid, lignan, moupinamide, sugiol, kaempferol and tanshinone IIa	Supress the M^pro and block the entrance, replication and fusion of the CoV Spike protein ³⁸
25.	Allium cepa and Liliaceae	Onion	Flavonols, quercetin glycosides, quercetin (quercitrin, isoquercitrin, and rutin) and kaempferol	Inhibit with different phases of the coronavirus entrance and replicating cycle, including PLpro, 3CL^pro, and NTPase/helicase. By competing with the precursor N-[3-(2-furyl) acryloyl] -L-phenylalanylglycylglycine, suppresses ACE ^{39, 40}
26.	Brassica oleracea and Brassicaceae	Broccoli	Glucosinolate type sinigrin	Stops the cleavage activity of M^proof CoV ⁴¹
27.	Veratrum sabadilla and Liliaceae	Lily plant	Sabadinine	Demonstrated to attach into M^pro's active region ⁴²
28.	Psidium guajava and Myrtaceae	Guava	Eugenol	High affinity for the M^pro and S proteins of CoV ⁴³
29.	Isatis indigotica and Brassicaceae	Dyer's woad	Aloe emodin and hesperetin	Reduced the cleavage effect of M^pro in a dose-dependent manner ⁴⁴
30.	Rheum palmatum and Polygonaceae	Chinese rhubarb	Ethyl acetate extract	In addition, an of Rheum palmatum and Polygonaceae, often recognized as, demonstrated anti-CoV-M^pro action ⁴⁵
31.	Toona sinensis and Meliaceae,and Pichia pastoris and Saccharomycetaceae	Chinese mahogany and Yeast	Quercetin	Inhibit the M^pro ^46,⁴⁷
32.	Thevetia peruviana and Apocynaceae and Nerium oleander	Yellow and Kaner Pink	Digitoxigenin	Inhibit the 3CL^proor M^pro ⁴⁸
33.	Camellia sinensis and Theaceae	Black tea	Theaflavin-30-O-gallate	Inhibit the 3CL^proor M^pro ⁴⁹
34.	Andrographis paniculata and Acanthaceae	Bitterweed	Andrographolide	Inhibit the 3CL^proor M^pro ⁵⁰
35.	Other species including Agaricus bisporus	Edible mushroom	Hispidin and Phellibaumins	Inhibit the 3CL^proor M^pro ⁵¹
36.	Origanum vulgare (Lamiaceae), Thymus vulgaris (Lamiaceae), Lepidium flavum (Brassicaceae), Citrus aurantium bergamia (Rutaceae)	Oregano, Thyme, Pepperwort, Wild bergamot	Carvacrol- phenolic monoterpenoid	Inhibit the 3CL^proor M^pro ⁵²

6. METHODS FOR SCREENING AND TESTING M^PRO INHIBITORS:

In this section, we will describe various in vitro and in silico methods that are used to screen and test bioactive metabolites for Main Protease (M^pro) inhibition, a crucial step in the development of potential COVID-19 treatments.

6.1 In vitro Methods:

6.1.1 Enzyme Assays:

6.1.1.1 Fluorogenic Substrate Assays: These assays use fluorogenic substrates that emit fluorescence upon cleavage by M^pro. Inhibitors that reduce fluorescence signal indicate M^pro inhibition⁵³.

6.1.1.2 Chromogenic Substrate Assays: Similar to fluorogenic assays, but using chromogenic substrates that change color upon cleavage⁵⁴.

6.1.2 Electrophoresis: Polyacrylamide Gel Electrophoresis (PAGE): This method separates proteins by size, allowing the detection of changes in M^pro mobility or conformation in the presence of inhibitors⁵⁵.

6.1.3 Mass Spectrometry: Liquid Chromato graphy-Mass Spectrometry (LC-MS): LC-MS can identify interactions between M^pro and inhibitors, providing information on binding affinity⁵⁶.

6.1.4 X-ray Crystallography: High-resolution structures of M^pro-inhibitor complexes can be obtained using X-ray crystallography, revealing the exact binding modes and interactions⁵⁷.

6.2 In silico Methods:

6.2.1 Molecular Docking: Molecular docking simulations predict the binding modes of bioactive metabolites within the active site of M^pro. It helps assess the affinity and potential inhibitory effects ⁵⁸.

6.2.2 Molecular Dynamics Simulations: These simulations analyse the dynamic behaviour of M^pro -inhibitor complexes over time. They provide insights into the stability of the interaction ⁵⁹.

6.2.3 Virtual Screening: Virtual screening involves the computational screening of large compound libraries to identify potential M^pro inhibitors based on molecular interactions and binding energies⁵⁸.

6.2.4 Quantitative Structure-Activity Relationship (QSAR) Modelling: QSAR models correlate the chemical structures of bioactive metabolites with their M^pro inhibitory activities, aiding in the design of more potent inhibitors ⁶⁰.

6.2.5 Pharmacophore Modelling: Pharmacophore models identify key chemical features required for M^pro inhibition, facilitating the screening of compound databases ⁶¹.

6.2.6 Machine Learning and AI Approaches: Machine learning algorithms and artificial intelligence can analyse large datasets of known M^pro inhibitors to predict potential inhibitors among bioactive metabolites ⁶².

6.3 Hybrid Approaches: Combining in vitro and in silico methods allows for a more comprehensive assessment of bioactive metabolites. Experimental data can validate computational predictions ⁶³.

7. CASE STUDIES:^64,65,66

Case Study 1: Quercetin

Bioactive Metabolite: Quercetin is a flavonoid found in various fruits and vegetables.

Experimental Results:

· In an in vitro study, quercetin was tested for its inhibitory effect on M^pro. The results showed a significant reduction in M^pro activity in the presence of quercetin.

· Molecular docking simulations confirmed the binding of quercetin to the active site of M^pro, where it forms hydrogen bonds with key catalytic residues.

· Further analysis using X-ray crystallography revealed the quercetin- M^pro complex's high-resolution structure, providing insights into the binding interactions.

Findings:

Quercetin demonstrated promising inhibitory activity against M^pro. Its ability to bind to the active site of M^pro and disrupt its catalytic function makes it a potential candidate for further development as an antiviral agent for COVID-19.

Case Study 2: Marine Sulphated Polysaccharides:

Bioactive Metabolite: Sulphated polysaccharides derived from marine sources.

Experimental Results:

· In vitro assays demonstrated the inhibition of M^pro activity in the presence of marine sulphated polysaccharides and verified by LC-MS measurements.

· According to the molecular dynamics tests, these substances block the enzymatic function of the M^pro-inhibitor compound by stabilising it.

Findings:

Marine sulphated polysaccharides have shown potential as M^pro inhibitors. Their ability to interact with and stabilize the enzyme-inhibitor complex suggests their value as natural compounds for further evaluation in COVID-19 drug development.

Case Study 3: Synthetic Protease Inhibitors:

Bioactive Metabolite: Lopinavir and Ritonavir, synthetic protease inhibitors.

Experimental Results:

In clinical trials, lopinavir and ritonavir were tested for their efficacy against SARS-CoV-2.

Results showed varying degrees of effectiveness in inhibiting viral replication and reducing the severity of COVID-19 symptoms in some patients.

Molecular docking studies indicated that lopinavir and ritonavir share structural similarities with fungal metabolites known for M^pro inhibition.

FINDINGS:

Lopinavir and ritonavir, while not natural bioactive metabolites, have been used in clinical settings due to their structural resemblance to fungal compounds known to inhibit M^pro. His antiviral capabilities in a few COVID-19 instances point to Mpro inhibition's possible use in the treatment of illness.

8. CHALLENGES AND FUTURE DIRECTIONS:

In this section, we will discuss the challenges and limitations in globally and the development of Main Protease (M^pro) inhibitors from bioactive metabolites and suggest potential future research directions and strategies for optimizing these compounds as COVID-19 treatments.

8.1 The covid-19 pandemic: a global challenge: ^67-84

The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has had a profound and far-reaching impact on the world, disrupting lives, economies, and societies on an unprecedented scale. The virus was initially identified in late 2019 in Wuhan, China. It quickly swept within the world, leading to widespread travel restrictions, lockdowns, and company closures. As of November 12, 2023, there have been over 660 million confirmed cases of COVID-19 and over 6.6 million deaths worldwide. The pandemic has had a significant impact on various aspects of human life, including:

8.1.1 Public Health: The COVID-19 virus is highly contagious and can cause severe respiratory illness, leading to hospitalization and death, particularly among older adults and those with underlying health conditions. Healthcare systems worldwide have been overwhelmed by the surge in COVID-19 patients, and many countries have faced shortages of personal protective equipment (PPE) and medical supplies.

8.1.2 Economy: The pandemic has caused a global economic recession, with widespread job losses, business closures, and disruptions in supply chains. According to ILO estimates, the epidemic would have lost the world market 255 million full-time employment opportunities by 2020.

8.1.3 Society: The pandemic has led to social isolation, loneliness, and mental health challenges. Many people have faced difficulties accessing essential services, such as food, healthcare, and education. Additionally, the global epidemic has made inequality worse by significantly impacting marginalised areas in terms of its implications for society and the economy.

Despite the challenges posed by the pandemic, there have been positive developments as well.

8.1.4 Scientific Advancements: Scientists have made rapid progress in understanding the COVID-19 virus and developing vaccines and treatments. Several effective vaccines have been developed and authorized for use, and they have played a crucial role in reducing the spread of the virus and protecting lives.

8.1.5 Global Cooperation: The pandemic has highlighted the need for international cooperation to address global challenges. Countries have worked together to develop and distribute vaccines, share information and resources, and coordinate public health measures.

8.1.6 Resilience and Innovation: People and communities around the world have shown remarkable resilience in the face of the pandemic. They have adapted to new ways of living and working, found innovative solutions to challenges, and supported one another through difficult times.

8.2 Challenges and Limitations: ^{85, 86, 87, 88}

8.2.1 Bioavailability and Pharmacokinetics:

· Many bioactive metabolites may have poor bioavailability, making it challenging to achieve effective concentrations in the body.

· Metabolism and rapid clearance can reduce the therapeutic potential of these compounds.

8.2.2 Safety and Toxicity: Bioactive metabolites may exhibit unexpected side effects or toxicity, necessitating rigorous safety assessments before clinical use.

8.2.3 Drug Interactions: Some bioactive metabolites may interact with other medications, potentially leading to adverse effects or reduced efficacy when used in combination.

8.2.4 Variability in Natural Sources: The composition of bioactive metabolites in natural sources can vary depending on factors like geographical location and environmental conditions, leading to inconsistency in compound availability and quality.

8.2.5 Resistance Development: The development of resistance to M^pro inhibitors is a concern, as it has been observed with other antiviral drugs.

8.2.6 Optimizing Inhibition: Identifying compounds with high selectivity and potency for M^pro inhibition is challenging, as the active site can be similar to other proteases.

8.3 Future Directions and Strategies:

8.3.1 Bioavailability Enhancement: Develop formulations or delivery methods that improve the bioavailability of bioactive metabolites to ensure effective therapeutic concentrations in the body.

8.3.2 Safety Profiling: Conduct extensive safety and toxicity assessments to understand the potential risks associated with bioactive metabolites and address any safety concerns.

8.3.3 Combinatorial Therapies: Explore the use of bioactive metabolites in combination with other antiviral agents to enhance efficacy and reduce the risk of resistance development.

8.3.4 Structure-Activity Relationship Studies: Conduct in-depth structure-activity relationship (SAR) studies to design and optimize bioactive metabolites specifically for M^pro inhibition.

8.3.5 Synthetic Derivatives: Develop synthetic derivatives of bioactive metabolites that retain M^pro inhibitory activity while addressing issues related to bioavailability and safety.

8.3.6 Natural Product Libraries: Continue screening and testing natural product libraries from diverse sources to identify novel bioactive metabolites with M^pro inhibitory potential.

8.3.7 Clinical Trials: Progress promising candidates to clinical trials to evaluate their safety and efficacy in humans, and potentially expedite their use as COVID-19 treatments.

8.3.8 Multidisciplinary Research: Collaborate with experts in various fields, including pharmacology, virology, and medicinal chemistry, to advance

9. CONCLUSION:

In conclusion, the current state of review on Main Protease (M^pro) inhibition by bioactive metabolites represents a promising avenue in the fight against COVID-19. Bioactive metabolites from various sources, including plants, fungi, and marine organisms, have shown significant potential as inhibitors of M^pro, a key enzyme in the replication of SARS-CoV-2. These compounds have been evaluated through a combination of in vitro and in silico methods, demonstrating their ability to disrupt M^pro 's enzymatic activity. Notable bioactive metabolites such as quercetin, marine sulphated polysaccharides, and synthetic protease inhibitors have displayed inhibitory effects on M^pro, opening the door to potential drug development. The optimising of bioactive compounds such as Mpro inhibitors has significant potential despite the obstacles of safety, obstruction, and absorption. The potential of bioactive metabolites in M^pro inhibition is not only significant for COVID-19 management but also holds promise for addressing emerging viral threats. The diverse range of bioactive metabolites and the specific targeting of M^pro represent an innovative approach that can contribute to the development of effective treatments against COVID-19 and other infectious diseases.

As the review process continues and substances move through clinical trials, bioactive compounds might be essential to the creation of antiviral medications, which would improve our ability to handle global health emergencies.

10. CONFLICT OF INTEREST:

There are no conflicts of interest for the authors in relation to this study.

11. ACKNOWLEDGMENTS:

The authors would like to thank School of Pharmacy, Chouksey Engineering College, Bilaspur, Chhattisgarh, Inida for their kind support during my studies.

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Received on 08.11.2023 Modified on 19.03.2024

Research J. Pharm. and Tech 2024; 17(9):4203-4213.

DOI: 10.52711/0974-360X.2024.00650