Withaferin A inhibits Chikungunya virus nsP2 protease and shows antiviral activity in the cell culture and mouse model of virus infection DOI Creative Commons
Kiran Bala Sharma, Chandru Subramani, Ganesh Kondabattula

и другие.

PLoS Pathogens, Год журнала: 2024, Номер 20(12), С. e1012816 - e1012816

Опубликована: Дек. 30, 2024

Chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus causing fever, myalgia, and debilitating joint swelling pain, which in many patients becomes chronic. The frequent epidemics of CHIKV across the world pose significant public health burden necessitating development effective antiviral therapeutics. A cellular imaging-based high-content screening natural compounds identified withaferin (WFA), steroidal lactone isolated from plant Withania somnifera, as potent against CHIKV. In ERMS cells, WFA inhibited replication early during life cycle by binding non-structural protein nsP2 inhibiting its protease activity. This viral polyprotein processing minus-sense RNA synthesis. mounted inhibitory activity through oxidising property reducing agents N-acetylcysteine Glutathione-monoethyl ester effectively reversed WFA-mediated inhibition vitro abolished cultured cells. C57BL/6 mouse model chikungunya disease, resulting significantly lower viremia. Importantly, CHIKV-infected mice showed was not seen WFA-treated mice. These data demonstrate potential novel antiviral.

Язык: Английский

Transformative Approaches in SARS-CoV-2 Management: Vaccines, Therapeutics and Future Direction DOI
Ankita Saha,

Shweta Choudhary,

Priyanshu Walia

и другие.

Virology, Год журнала: 2025, Номер 604, С. 110394 - 110394

Опубликована: Янв. 11, 2025

Язык: Английский

Процитировано

1
Structural and Mechanistic Insights into the Main Protease (Mpro) Dimer Interface Destabilization Inhibitor: Unveiling New Therapeutic Avenues against SARS-CoV-2 DOI
Ankur Singh,

Kuldeep Jangid,

Sanketkumar Nehul

и другие.

Biochemistry, Год журнала: 2025, Номер unknown

Опубликована: Янв. 30, 2025

SARS-CoV-2 variant recurrence has emphasized the imperative prerequisite for effective antivirals. The main protease (Mpro) of is crucial viral replication, making it one prime and promising antiviral targets. Mpro features several druggable sites, including active sites allosteric near dimerization interface, that regulate its catalytic activity. This study identified six highly efficacious compounds (WIN-62577, KT185, bexarotene, ledipasvir, diacerein, simepervir) using structure-based virtual screening compound libraries against Mpro. Using SPR ITC, binding selected inhibitory to target was validated. FRET-based assay demonstrated molecules effectively inhibit with IC50 values in range from 0.64 11.98 μM. Additionally, vitro cell-based assays showed high efficacy EC50 1.51 18.92 crystal structure Mpro-minocycline complex detailed possible inhibition mechanism minocycline, an FDA-approved antibiotic. Minocycline binds site, revealing residues critical loss activity due destabilization molecular interactions at dimeric which are proteolytic suggests minocycline site may play a role dimer direct rational design derivatives as drugs.

Язык: Английский

Процитировано

1
Bioactive Alkaloids in Azadirachta indica Seed and Their Biological Activities DOI

Kartik Chandra Guchhait,

Subhamoy Dey,

Ankita Das

и другие.

Springer eBooks, Год журнала: 2025, Номер unknown, С. 1 - 25

Опубликована: Янв. 1, 2025

Язык: Английский

Процитировано

0
Structural Virology: The Key Determinants in Development of Antiviral Therapeutics DOI Creative Commons
Tanuj Handa, Ankita Saha, Aarthi Narayanan

и другие.

Viruses, Год журнала: 2025, Номер 17(3), С. 417 - 417

Опубликована: Март 14, 2025

Structural virology has emerged as the foundation for development of effective antiviral therapeutics. It is pivotal in providing crucial insights into three-dimensional frame viruses and viral proteins at atomic-level or near-atomic-level resolution. Structure-based assessment components, including capsids, envelope proteins, replication machinery, host interaction interfaces, instrumental unraveling multiplex mechanisms infection, replication, pathogenesis. The structural elucidation enzymes, proteases, polymerases, integrases, been essential combating like HIV-1 HIV-2, SARS-CoV-2, influenza. Techniques X-ray crystallography, Nuclear Magnetic Resonance spectroscopy, Cryo-electron Microscopy, Tomography have revolutionized field significantly aided discovery ubiquity chronic infections, along with emergence reemergence new threats necessitate novel strategies agents, while extensive diversity their high mutation rates further underscore critical need analysis to aid development. This review highlights significance structure-based investigations bridging gap between structure function, thus facilitating therapeutics, vaccines, antibodies tackling emerging threats.

Язык: Английский

Процитировано

0
Mechanistic Insights into Targeting SARS-CoV-2 Papain-like Protease in the Evolution and Management of COVID-19 DOI Creative Commons

Nonjabulo Ntombikhona Magwaza,

Aganze Gloire-Aimé Mushebenge, Samuel Chima Ugbaja

и другие.

BioChem, Год журнала: 2024, Номер 4(3), С. 268 - 299

Опубликована: Сен. 23, 2024

The COVID-19 pandemic, instigated by the emergence of novel coronavirus, SARS-CoV-2, created an incomparable global health crisis. Due to its highly virulent nature, identifying potential therapeutic agents against this lethal virus is crucial. PLpro a key protein involved in viral polyprotein processing and immune system evasion, making it prime target for development antiviral drugs combat COVID-19. To expedite search candidates, review delved into computational studies. Recent investigations have harnessed methods identify promising inhibitors targeting PLpro, aiming suppress activity. Molecular docking techniques were employed researchers explore binding sites within catalytic region PLpro. elucidates functional structural properties SARS-CoV-2 underscoring significance pathogenicity replication. Through comprehensive all-atom molecular dynamics (MD) simulations, stability drug–PLpro complexes was assessed, providing dynamic insights their interactions. By evaluating energy estimates from MD stable with identified. This offers overview drug/lead candidates discovered thus far using diverse silico methodologies, encompassing drug repurposing, structure-based, ligand-based virtual screenings. Additionally, identified are listed based on chemical structures meticulously examined according various parameters, such as estimated free (ΔG), types intermolecular interactions, PLpro–ligand complexes, determined outcomes simulations. Underscoring pivotal role battle COVID-19, establishes robust foundation integrating modeling, insights. continual imperative improvement existing exploring compounds remains paramount efforts evolution management hinge symbiotic relationship between experimental validation, interdisciplinary synergy crucial endeavor.

Язык: Английский

Процитировано

2
Disruption of Molecular Interactions between the G3BP1 Stress Granule Host Protein and the Nucleocapsid (NTD-N) Protein Impedes SARS-CoV-2 Virus Replication DOI

Preeti Dhaka,

Ankur Singh, Sanketkumar Nehul

и другие.

Biochemistry, Год журнала: 2024, Номер unknown

Опубликована: Дек. 21, 2024

The Ras GTPase-activating protein SH3-domain-binding 1 (G3BP1) serves as a formidable barrier to viral replication by generating stress granules (SGs) in response infections. Interestingly, viruses, including SARS-CoV-2, have evolved defensive mechanisms hijack SG proteins like G3BP1 for the dissipation of SGs that lead evasion host's immune responses. Previous research has demonstrated interaction between NTF2-like domain (G3BP1NTF-2) and intrinsically disordered N-terminal (NTD-N1-25) N-protein plays crucial role regulating pathogenicity. current study identified an additional upstream stretch residues (128KDGIIWVATEG138) (N128-138) within (NTD-N41-174) also forms molecular contacts with protein, revealed through silico analysis, site-directed mutagenesis, biochemical analysis. Remarkably, WIN-62577, fluspirilene, small molecules targeting conserved peptide-binding pocket G3BP1NTF-2, not only disrupted protein-protein interactions (PPIs) NTD-N41-174 G3BP1NTF-2 but exhibited significant antiviral efficacy against SARS-CoV-2 EC50 values ∼1.8 ∼1.3 μM, respectively. findings this study, validated biophysical thermodynamics investigations, advance potential developing therapeutics host which may serve broad-spectrum target.

Язык: Английский

Процитировано

2
Structure-based virtual screening methods for the identification of novel phytochemical inhibitors targeting furin protease for the management of COVID-19 DOI Creative Commons
Prashant Kumar Tiwari, Mandeep Chouhan, Richa Mishra

и другие.

Frontiers in Cellular and Infection Microbiology, Год журнала: 2024, Номер 14

Опубликована: Июнь 11, 2024

The coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome 2 (SARS-CoV-2) virus, is a highly contagious with widespread societal impact. symptoms range from cough, fever, and pneumonia to complications affecting various organs, including heart, kidneys, nervous system. Despite ongoing efforts, no effective drug has been developed stop spread of virus. Although types medications used treat bacterial viral diseases have previously employed COVID-19 patients, their side effects also observed. way SARS-CoV-2 infects human body very specific, as its spike protein plays an important role. S subunit virus cleaved proteases, such furin protein, initial step for internalization into host. Keeping this context, we attempted inhibit using phytochemicals that could produce minimal effects. For this, screened 408 natural plants having antiviral properties, against molecular docking dynamics simulations were performed. Based on binding score, top three compounds (robustaflavone, withanolide, amentoflavone) selected further validation. MM/GBSA energy calculations revealed withanolide lowest -57.2 kcal/mol followed robustaflavone amentoflavone -45.2 -39.68 kcal/mol, respectively. Additionally, ADME analysis showed drug-like properties these lead compounds. Hence, robustaflavone, amentoflavone, may therapeutic potential management targeting furin.

Язык: Английский

Процитировано

1
Crystal structure and activity profiling of deubiquitinating inhibitors-bound to SARS-CoV-2 papain like protease revealed new allosteric sites for antiviral therapies DOI Creative Commons

Shweta Choudhary,

Sanketkumar Nehul, Santhosh Kambaiah Nagaraj

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2022, Номер unknown

Опубликована: Ноя. 11, 2022

Abstract SARS-CoV-2 papain-like protease (PLpro) is a key antiviral target as it plays dual role in viral replication and modulation of innate immune responses by deubiquitinating or deISGylating host proteins. Thus, therapeutic targeting PLpro serves two-pronged approach to abate SARS-CoV-2. Interestingly, shares structural functional similarities with the cellular enzymes (DUBs) this study fact has been exploited identify DUBs inhibitors that Ubiquitin/ISG15 binding site known catalytic substrate pocket PLpro. Among these identified compounds, flupenthixol, lithocholic acid, teneligliptin, linagliptin markedly inhibited proteolytic activity purified demonstrated potent efficacies against infection dose dependent manner. Treatment acid suppressed expression levels inflammatory mediators, thereby, restoring responses. Crystal structures complex determined study, revealed insights into inhibition mechanism unique interactions within (S2 site; Phe69, His73, Asn128, His175) cleft. Additionally, oral intraperitoneal treatments increased survival, reduced lung load, ameliorated histopathological damage mouse-adapted model infection. The for first time demonstrates strategy using DUB simultaneously reinstates host’s response

Язык: Английский

Процитировано

7
Withaferin A inhibits Chikungunya virus nsP2 protease and shows antiviral activity in the cell culture and mouse model of virus infection DOI Creative Commons
Kiran Bala Sharma, Chandru Subramani, Ganesh Kondabattula

и другие.

PLoS Pathogens, Год журнала: 2024, Номер 20(12), С. e1012816 - e1012816

Опубликована: Дек. 30, 2024

Chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus causing fever, myalgia, and debilitating joint swelling pain, which in many patients becomes chronic. The frequent epidemics of CHIKV across the world pose significant public health burden necessitating development effective antiviral therapeutics. A cellular imaging-based high-content screening natural compounds identified withaferin (WFA), steroidal lactone isolated from plant Withania somnifera, as potent against CHIKV. In ERMS cells, WFA inhibited replication early during life cycle by binding non-structural protein nsP2 inhibiting its protease activity. This viral polyprotein processing minus-sense RNA synthesis. mounted inhibitory activity through oxidising property reducing agents N-acetylcysteine Glutathione-monoethyl ester effectively reversed WFA-mediated inhibition vitro abolished cultured cells. C57BL/6 mouse model chikungunya disease, resulting significantly lower viremia. Importantly, CHIKV-infected mice showed was not seen WFA-treated mice. These data demonstrate potential novel antiviral.

Язык: Английский

Процитировано

0