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Medicinal Plants Against COVID-19
Published in Hanadi Talal Ahmedah, Muhammad Riaz, Sagheer Ahmed, Marius Alexandru Moga, The Covid-19 Pandemic, 2023
Binish Khaliq, Naila Ali, Ahmed Akrem, M. Yasin Ashraf, Arif Malik, Arifa Tahir, M. Zia-Ul-Haq
To use the natural molecules in edible plants properly against the coronavirus disease-19, it is mandatory to have an understanding of structural targets, receptors, and their mechanism of action associated with this virus. Seven human coronaviruses (HCoVs) have been identified till now and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) also have +ssRNA along with two protein groups: structural protein and non-structural protein; structural protein included spike, envelope, matrix, and nucleocapsid while non-structural proteins comprised of nsp12-RNA-dependent RNA polymerase (RdRp), Nsp3-Papain-like proteinases, Nsp5-3C-like main protease and nsP13 SARS-CoV helicase [156, 157]. Despite of these proteins, human angiotensin-converting-enzyme-2 (ACE-2) act as a receptor of SARS-CoV-2 as essentially present in the lungs, heart, intestine, kidneys, and blood vessels can be targeted to prevent the entry of viruses into the host cells [158, 159]. The functioning of angiotensin-converting-enzyme-2 increased exponentially in diabetic patients as well as in the patients suffering from hypertension. This ACE-2 is actually a site for the replication of viruses soil the interest of developing the drugs to suppress this receptor is increasing [160]. Many plants have been reported containing phytochemicals effectively targeting viral diseases like SARS, HIV, HCV, etc. [23, 161].
Rotavirus
Published in Dongyou Liu, Handbook of Foodborne Diseases, 2018
Lijuan Yuan, Tammy Bui, Ashwin Ramesh
Circularization of mRNA is necessary for efficient translation to produce viral protein products. This process is dependent on the binding of the highly conserved genogroup specific consensus sequence (such as 5′-GUGACC-3′ in RVA) to the N-terminal region of NSP3. The NSP3 C-terminal region interacts with the host eukaryotic translation initiation factor 4G, resulting in a circular mRNA product.38,39 dsRNA viral genome synthesis occurs in cytoplasmic inclusion bodies called viroplasm whose formation depends on the colocalization of NSP2 and NSP5, together with lipid droplets.31,40,41
Nitazoxanide
Published in M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson, Kucers’ The Use of Antibiotics, 2017
Cell culture experiments with rotavirus have demonstrated that tizoxanide is cytoprotective and inhibits viral replication (Rossignol et al., 2006a). La Frazia et al. investigated the mechanism of antirotavirus activity of nitazoxanide and found that nitazoxanide and tizoxanide inhibited human and simian rotaviruses in vitro by interfering with viral morphogenesis. Specifically, nitazoxanide interferes with the interaction of rotavirus nonstructural proteins NSP5 and NSP2, altering the size and architecture of viroplasms and blocking virus dsRNA replication and packaging. These investigators reported IC50 values of nitazoxanide between 0.3 and 2 μg/ml in multiple cell lines—concentrations that are attainable in the serum and gastrointestinal tracts of humans treated with oral nitazoxanide (La Frazia et al., 2013).
Natural history of COVID-19 and therapeutic options
Published in Expert Review of Clinical Immunology, 2020
Philippe Gautret, Matthieu Million, Pierre-André Jarrot, Laurence Camoin-Jau, Philippe Colson, Florence Fenollar, Marc Leone, Bernard La Scola, Christian Devaux, Jean Yves Gaubert, Jean-Louis Mege, Joana Vitte, Cléa Melenotte, Jean-Marc Rolain, Philippe Parola, Jean-Christophe Lagier, Philippe Brouqui, Didier Raoult
SARS-CoV-2 is an enveloped RNA surrounded by spike glycoproteins [46–49]. The virus enters cells through membrane fusion. The first step of the SARS-CoV-2 replicative cycle is the attachment of the virus to the angiotensin-converting enzyme 2 (ACE2) glycoprotein. The receptor-binding domain (RBD) amino acid sequences present in the S1 spike protein interact with the N-terminal region 30–41 and 82–93 of ACE2 that contains several sites for N-glycosylation. A cell-surface protease, TMPRSS2, is responsible for spike cleavage allowing the appropriate conformation for the S2 spike to expose the hidden fusion peptide for insertion into the cellular membrane lipid bilayers. The viral nucleocapsid is thus delivered into the cytoplasm through the endocytic vesicle. After acidification of the late endosome, the action of cathepsin enables the uncoating of the genomic RNA and the enzymes necessary for its replication. The genomic RNA is used as a template by the replicase to synthesize the negative-sense genomic RNAs (anti-genome), which are used as templates to synthesize the progeny positive sense genomes and subgenomic RNAs. Similarly to SARS-CoV, the 5ʹ-proximal two-thirds of the SARS-CoV-2 viral genome are translated into polyproteins that give rise to several nonstructural proteins (Nsps) following autoproteolytic processing. Among the Nsps, Nsp12 is an RNA-dependent RNA polymerase, Nsp3 and Nsp5 are proteinases, Nsp13 is a helicase, Nsp14 and Nsp15 are ribonucleases, and Nsp14 is a methyltransferase (involved in RNA cap formation). The 3ʹ-proximal third sequence serves as template for several subgenomic mRNAs that encode the viral structural (the spike/S, the envelope/E, the membrane/M, and the nucleocapsid/N) and accessory proteins. The S, E and M proteins are synthesized and anchored on the endoplasmic reticulum (ER) with the N protein translated in the cytosol. Posttranslational modifications of viral proteins occur within the endoplasmic reticulum and trans-Golgi network vesicles. After assembly in the ER-Golgi intermediate compartment (ERGIC), where the E protein plays an essential role in virus assembly and the mature M protein shapes the virus, mature virions are released from smooth-walled vesicles by exocytosis.
Inhibition of SARS-CoV 3CL protease by flavonoids
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Seri Jo, Suwon Kim, Dong Hae Shin, Mi-Sun Kim
The custom-synthesised fluorogenic substrate, DABCYL-KTSAVLQSGFRKME-EDANS (ANYGEN, Gwangju, Korea), was used as a substrate for the proteolytic assay using the SARS-CoV 3CLpro18. This substrate contains the nsp4/nsp5 cleavage sequence, GVLQ↓SG19, and works as a generic peptide substrate for many coronavirus including the SARS-CoV 3CLpro. The peptide was dissolved in distilled water and incubated with each protease. A SpectraMax i3x Multi-mode microplate reader (Molecular Devices) was used to measure spectral-based fluorescence. The proteolytic activity was determined at 310 K by following the increase in fluorescence (λexcitation = 340 nm, λemission = 490 nm, bandwidths = 9, 15 nm, respectively) of EDANS upon peptide hydrolysis as a function of time. Assays were conducted in black, 96-well plates (Nunc) in 300 μl assay buffers containing protease and substrate as follow; For the SARS-CoV 3CLpro assay, 4.05 μl of 0.074 mM protease containing 50 mM Tris pH 6.5 was incubated with 7.5 μl of 0.1 mM substrate at 310 K for 2 h before measuring Relative Fluorescence Unit (RFU). Before the assay, the emission spectra of 64 flavonoids were surveyed after illuminating at 340 nm to avoid the overlapping with the emission spectrum of EDANS. Every compound was suitable to be tested. The final concentration of the protease, peptide and chemical used at the assay was 1, 2.5 and 20 μM each. At first, the SARS-CoV 3CLpro and chemical were mixed and pre-incubated at room temperature for 1 h. The reaction was initiated by the addition of the substrate and each well was incubated at 310 K for 16 h. After that, we measured the fluorescence of the mixture on the black 96-well plate using the endpoint mode of SpectraMax i3x where the excitation wavelength was fixed to 340 nm and the emission wavelength was set to 490 nm using 9, 15 nm bandwidth, respectively. All reactions were carried out in triplicate. Among the first 64 flavonoids (Supplementary Table 1), three of them were picked up to further assay at a concentration range of 2–320 μM. The IC50 value which is the value causing 50% inhibition of the catalytic activity of the SARS-CoV 3CLpro was calculated by nonlinear regression analysis using GraphPad Prism 7.03 (GraphPad Software, San Diego, CA, USA).
Flavonoids with inhibitory activity against SARS-CoV-2 3CLpro
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Seri Jo, Suwon Kim, Dae Yong Kim, Mi-Sun Kim, Dong Hae Shin
The custom-synthesised fluorogenic substrate, DABCYL-KTSAVLQSGFRKME-EDANS (ANYGEN, Gwangju, Korea), was used as a substrate for the proteolytic assay using the SARS-CoV-2 3CLpro9. This substrate contains the nsp4/nsp5 cleavage sequence, GVLQ↓SG10, and works as a generic peptide substrate for many coronaviruses including the SARS-CoV-2 3CLpro. The peptide was dissolved in distilled water and incubated with each protease. A SpectraMax i3x Multi-mode microplate reader (Molecular Devices) was used to measure spectral-based fluorescence. The proteolytic activity was determined at 310 K by following the increase in fluorescence (λexcitation = 340 nm, λemission = 490 nm, bandwidths = 9, 15 nm, respectively) of EDANS upon peptide hydrolysis as a function of time. Assays were conducted in black, 96-well plates (Nunc) in 300 μl assay buffers containing protease and substrate as follow; For the SARS-CoV-2 3CLpro assay, 2.04 μl of 0.294 mM protease containing 20 mM Tris pH 7.5 was incubated with 7.5 μl of 0.1 mM substrate at 310 K for 2 h 30 min before measuring Relative Fluorescence Units (RFU). Before the assay, the emission spectra of antiviral agents and some of their adjuvants were surveyed after illuminating at 340 nm to avoid the overlapping with the emission spectrum of EDANS. Every compound was suitable to be tested. The final concentration of the protease, peptide, and chemical used at the assay was 2 µM, 2.5 µM and 80 µM each. At first, SARS-CoV-2 3CLpro and chemical were mixed and preincubated at room temperature for 1 h. The reaction was initiated by the addition of the substrate and each well was incubated at 310 K for 2 h 30 min. After that, we measured the fluorescence of the mixture on the black 96-well plate using the endpoint mode of SpectraMax i3x where the excitation wavelength was fixed to 340 nm and the emission wavelength was set to 490 nm using 9, 15 nm bandwidth, respectively. All reactions were carried out in triplicate. Among the first seventy flavonoids (Supplementary Table 1), one of them was picked up to further assay at a concentration range of 4 µM ∼ 240 µM. The IC50 value which is the value causing 50% inhibition of SARS-CoV-2 3CLpro was calculated by nonlinear regression analysis using GraphPad Prism 7.03 (GraphPad Software, San Diego, CA, USA).