Development and Validation of In-vitro Release Study of Molnupiravir Capsules by RP-HPLC DOI
Shipra Singhal, Aman Sharma,

Anirudh Malik

et al.

Current Pharmaceutical Analysis, Journal Year: 2023, Volume and Issue: 19(7), P. 577 - 585

Published: Aug. 22, 2023

Introduction: The coronavirus disease-2019 (COVID-19) outbreak all over the world has led researchers to strive develop treatment and preventive measures control its progression. Methods: Molnupiravir, a prodrug of synthetic nucleoside derivative N-4-hydroxycytidine was found be promising candidate against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Results: It could significantly reduce risk hospitalization mortality among patients with positive SARS-CoV-2 reports. In this study, an RP-HPLC method UV detection developed determine dissolution release in capsule dosage form. validated as per International Council for Harmonization (ICH) guidelines. Conclusion: evaluated applicability using various parameters. simple, rapid, selective, sensitive, accurate, precise, robust rugged method.

Language: Английский

Synthesis and anti-SARS-CoV-2 evaluation of lipid prodrugs of β-D-N4-hydroxycytidine (NHC) and a 3′-fluoro-substituted analogue of NHC DOI Open Access

Zhaohui Wen,

Mengmeng Wang, Lingyun Li

et al.

Bioorganic Chemistry, Journal Year: 2023, Volume and Issue: 135, P. 106527 - 106527

Published: April 6, 2023

Language: Английский

Citations

5
In vitro testing of host-targeting small molecule antiviral matriptase/TMPRSS2 inhibitors in 2D and 3D cell-based assays DOI Open Access
Nicholas van Eijk, Luna C. Schmacke, Torsten Steinmetzer

et al.

Biomedicine & Pharmacotherapy, Journal Year: 2023, Volume and Issue: 168, P. 115761 - 115761

Published: Oct. 20, 2023

The outbreak of coronavirus disease 2019 (COVID-19) pandemic strongly stimulated the development small molecule antivirals selectively targeting type II transmembrane serine proteases (TTSP), required for host-cell entry numerous viruses. A set 3-amidinophenylalanine derivatives (MI-21, MI-472, MI-477, MI-485, MI-1903 and MI-1904), which inhibit cleavage certain viral glycoproteins was characterized in 2D 3D primary human hepatocyte models on collagen- Matrigel-coating using a CCK-8 assay to evaluate their cytotoxicity, resorufin-based method detect redox imbalances, fluorescence ultrafiltration experiments interactions with serum albumin (HSA) α-acidic glycoprotein (AGP), luminescence measurement assess CYP3A4 modulation. For elucidation selectivity applied compounds towards matriptase, protease 2 (TMPRRS2), thrombin factor Xa (FXa) Ki values were determined. It proven that cell viability only deteriorated by inhibitor MI-1903, status not influenced administration selected inhibitors at 50 µM 24 h. MI-472 MI-477 formed relatively stable complexes AGP. inhibition found be strong PHHs exposed all exception MI-21, seems promising drug candidate also due its better matriptase TMPRSS2 over blood clotting FXa. Our vitro pharmacokinetic screening these helps select best safety profile suitable further preclinical characterization without animal sacrifice.

Language: Английский

Citations

5
Exploring nucleoside analogs: key targets in the viral life cycle - advancing strategies against SARS-CoV-2 DOI
Roopal Garg,

Raveen Kumar,

Ritika Srivastava

et al.

Medicinal Chemistry Research, Journal Year: 2024, Volume and Issue: 33(6), P. 869 - 884

Published: May 28, 2024

Language: Английский

Citations

1
Ultrasound-assisted preparation of zein particles: Insight into the effects and mechanisms of thermal factors DOI

Wujun You,

Hongge Liu,

Benjamin Ndeshipanda Kashenye

et al.

Innovative Food Science & Emerging Technologies, Journal Year: 2024, Volume and Issue: unknown, P. 103825 - 103825

Published: Sept. 1, 2024

Language: Английский

Citations

1
The effects of Remdesivir’s functional groups on its antiviral potency and resistance against the SARS-CoV-2 polymerase DOI Creative Commons
Bhawna Sama, Barbara Selisko, Camille Falcou

et al.

Antiviral Research, Journal Year: 2024, Volume and Issue: 232, P. 106034 - 106034

Published: Nov. 5, 2024

Remdesivir (RDV, Veklury®) is the first FDA-approved antiviral treatment for COVID-19. It a nucleotide analogue (NA) carrying 1'-cyano (1'-CN) group on ribose and pseudo-adenine nucleobase whose contributions to mode of action (MoA) are not clear. Here, we dissect these independent by employing RDV-TP analogues. We show that while 1'-CN directly responsible transient stalling SARS-CoV-2 replication/transcription complex (RTC), plays role in strength this stalling. Conversely, RNA extension assays fidelity can be incorporated as GTP analogue, albeit with lower efficiency. However, mutagenic effect viral polymerase ascertained deep sequencing from cells treated RDV. observe once added 3' end RNA, RDV-MP sensitive excision its does impact nsp14-mediated removal. A >14-fold RDV-resistant isolate selected two mutations nsp12 sequence, S759A A777S. They confer both discrimination over ATP during synthesis, leaving more time excision-repair potentially dampening RDV conclude presents multi-faced MoA. slows down or stalls overall synthesis but efficiently repaired primer strand, whereas template, read-through inhibition adds effect. Its efficient incorporation may corrupt proviral likely disturbing downstream functions virus life cycle.

Language: Английский

Citations

1
An exonuclease-resistant chain-terminating nucleotide analogue targeting the SARS-CoV-2 replicase complex DOI Creative Commons
Ashleigh Shannon, Aurélie Chazot, Mikaël Feracci

et al.

Nucleic Acids Research, Journal Year: 2023, Volume and Issue: 52(3), P. 1325 - 1340

Published: Dec. 12, 2023

Nucleotide analogues (NA) are currently employed for treatment of several viral diseases, including COVID-19. NA prodrugs intracellularly activated to the 5'-triphosphate form. They incorporated into RNA by polymerase (SARS-CoV-2 nsp12), terminating or corrupting synthesis. For Coronaviruses, natural resistance NAs is provided a 3'-to-5' exonuclease heterodimer nsp14/nsp10, which can remove terminal analogues. Here, we show that replacement α-phosphate Bemnifosbuvir form (AT-9010) an α-thiophosphate renders it resistant excision. The resulting α-thiotriphosphate, AT-9052, exists as two epimers (RP/SP). Through co-crystallization and activity assays, Sp isomer preferentially used substrate nucleotide diphosphate kinase (NDPK), SARS-CoV-2 nsp12, where its incorporation causes immediate chain-termination. same -Sp isomer, once also totally excision nsp10/nsp14 complex. However, unlike AT-9010, AT-9052-RP/SP no longer inhibits N-terminal nucleotidylation domain nsp12. We conclude AT-9052-Sp exhibits unique mechanism action against SARS-CoV-2. Moreover, thio modification provides general approach rescue existing whose hampered coronavirus proofreading capacity.

Language: Английский

Citations

3
Structural and Synthetic Aspects of Small Ring Oxa- and Aza-Heterocyclic Ring Systems as Antiviral Activities DOI Creative Commons

Sibasish Manna,

Koushik K. Das, Sougata Santra

et al.

Viruses, Journal Year: 2023, Volume and Issue: 15(9), P. 1826 - 1826

Published: Aug. 28, 2023

Antiviral properties of different oxa- and aza-heterocycles are identified properly correlated with their structural features discussed in this review article. The primary objective is to explore the activity such ring systems as antiviral agents, well synthetic routes biological significance. Eventually, structure–activity relationship (SAR) heterocyclic compounds, along salient characteristics exhibited build a suitable platform for medicinal chemists biotechnologists. synergistic conclusions extremely important introduction newer tool future drug discovery program.

Language: Английский

Citations

2
Oligomeric State of β-Coronavirus Non-Structural Protein 10 Stimulators Studied by Small Angle X-ray Scattering DOI Open Access
Wolfgang Knecht, S. Zoë Fisher, Jiaqi Lou

et al.

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(17), P. 13649 - 13649

Published: Sept. 4, 2023

The β-coronavirus family, encompassing Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), (SARS), and Middle East (MERS), has triggered pandemics within the last two decades. With possibility of future pandemics, studying coronavirus family members is necessary to improve knowledge treatment. These viruses possess 16 non-structural proteins, many which play crucial roles in viral replication other vital functions. One such protein 10 (nsp10), acting as a pivotal stimulator nsp14 nsp16, thereby influencing RNA proofreading cap formation. Studying nsp10 pathogenic coronaviruses central unraveling its multifunctional roles. Our study involves biochemical biophysical characterisation full-length from MERS, SARS SARS-CoV-2. To elucidate their oligomeric state, we employed combination Multi-detection Size exclusion chromatography (Multi-detection SEC) with multi-angle static light scattering (MALS) small angle X-ray (SAXS) techniques. findings reveal that nsp10s primarily exist monomers solution, while truncated versions tend oligomerise. SAXS experiments globular shape for nsp10, trait conserved all three coronaviruses, although MERS diverges most SARS-CoV-2 nsp10s. In summary, unbound proteins SARS, exhibit predominantly monomeric state solution.

Language: Английский

Citations

1
Synthesis and Antiviral Activity of Novel β-D-N4-Hydroxycytidine Ester Prodrugs as Potential Compounds for the Treatment of SARS-CoV-2 and Other Human Coronaviruses DOI Creative Commons
E.S. Darnotuk, Andrei E. Siniavin,

Natal’ya S. Shastina

et al.

Pharmaceuticals, Journal Year: 2023, Volume and Issue: 17(1), P. 35 - 35

Published: Dec. 26, 2023

The spread of COVID-19 infection continues due to the emergence multiple transmissible and immune-evasive variants SARS-CoV-2 virus. Although various vaccines have been developed several drugs approved for treatment COVID-19, development new combat is still necessary. In this work, 5'-O-ester derivatives N4-hydroxycytidine based on carboxylic acids were synthesized by Steglich esterification. antiviral activity compounds was assessed in vitro-inhibiting cytopathic effect HCoV-229E, three SARS-CoV-2, huh-7 Vero E6 cells. Data shown that most exhibit high against coronaviruses. addition, relationship between chemical structure their has established. obtained results show active compound conjugate SN_22 3-methyl phenoxyacetic acid. study indicate potential advantage strategies used modify NHC as a promising avenue be explored vivo, which could lead with improved pharmacological properties potently inhibit SARS-CoV-2.

Language: Английский

Citations

1
The activation chain of the broad-spectrum antiviral bemnifosbuvir at atomic resolution DOI Creative Commons
Aurélie Chazot, Claire Zimberger, Mikaël Feracci

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Feb. 16, 2024

Bemnifosbuvir (AT-527) and AT-752 are guanosine analogues currently in clinical trials against several RNA viruses. Here we show that these drugs require a minimal set of 5 cellular enzymes for activation to their common 5'-triphosphate AT-9010, with an obligate order reactions. AT-9010 selectively inhibits essential viral enzymes, accounting broad spectrum antiviral potency. Functional structural data at atomic resolution decipher N6-purine deamination compatible metabolic by human ADALP1. Crystal structures HINT1, ADALP1, GUK1, NDPK 2.09, 2.44, 1.76, 1.9 A resolution, respectively, cognate precursors illuminate the pathway from orally available bemnifosbuvir pointing key drug-protein contacts along pathway. Our work provides framework integrate design nucleotide analogues, confronting requirements constraints associated assembly line.

Language: Английский

Citations

0