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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].
SARS-CoV Infections in Humans
Published in Sunit K. Singh, Human Respiratory Viral Infections, 2014
Newly formed viral replicative proteins are anchored to intracytoplasmic membranous structures. There is extensive posttranslational processing of the nonstructural proteins. In contrast to other coronaviruses, SARS-CoV used a single papain-like protease PL2pro, instead of the usual two enzymes PL1pro and PL2pro in other coronaviruses, for processing the N-terminal side of the replicative polyprotein at three specific sites. PL2pro of SARS-CoV also has unusually narrow substrate specificity, as compared to homologues of other coronaviruses.12,30–38 The central portion and C-terminal end of the polyprotein are processed by a chymotrypsin-like protease 3CLpro at 11 specific sites.34,39,40 This protease is also known as the main protease, Mpro, as it releases the enzymes, RNA-dependent RNA polymerase (RdRp, nsp12) and helicase (nsp13), with both of these latter proteins being very important to viral replication. There are altogether 16 replicase gene products (nsp1 to nsp16). These nonstructural proteins range in size, from 13 to 1922 amino acid residues. Some of these proteins have novel predicted functions, including an ADP-ribose 1′-phosphatase activity (nsp3), 3′-to-5′ exonuclease activity (nsp14), uridylate-specific endoribonuclease (nsp15), and S-adenosylmethioine-dependent 2′-O-phosphatase (nsp16). As much as five of these nsp proteins have no known or predicted functions.41–44
Coronavirus Epidemics and the Current COVID-19 Pandemic
Published in Debmalya Barh, Kenneth Lundstrom, COVID-19, 2022
Aparna Bhardwaj, Prateek Kumar, Shivani Krishna Kapuganti, Vladimir N. Uversky, Rajanish Giri
Since the S protein is exposed and involved in the first step of host cell infection, it is the main therapeutic target for neutralizing antibodies [42]. Apart from the S protein, the E protein, and other proteins can be targets for protein-based vaccines or for virus-like particle (VLP) systems. The E protein is essential for the pathogenicity and mortality caused by the virus, as confirmed by studies in animal models [43]. The M protein is complexed with the host immune components like HLA1 and β2-microglobulin, and has also been reported to be a potential target [68]. Three ion channel-forming proteins (E, ORF3a, and ORF8) offer good targets, as these enhance the pathogenicity of the virus by altering the ionic balance in host cells [50]. The active replication complex (NSP12-NSP8-NSP7) is the main target for inhibition of virus growth, as it is the key enzyme for virus survival [63]. The NSP12 is the main target for drugs in this complex, but mutations rendering the virus resistant to drugs have been described [69]. The current antiviral approaches use the S protein and the two proteases, NSP3 (papain-like protease) and NSP5 (3CL protease), as the main targets. However, these strategies can cause severe side effects, as they act non-specifically on host cellular proteases [48]. As NSP15 acts as an endoribonuclease its uridine-binding active site has been used as a drug target because of its effect on host immunity. Tipiracil, a synthesized drug that is a uridine analogue derived from uridine itself, binds to the active site of NSP15 and inhibits its activity [67]. Computational drug screening and simulation studies have been carried out against multiple targets of SARS-CoV and SARS-CoV-2, such as the S protein, proteases, helicases, RdRp, etc. [70, 71]. Moreover, computational methods have been applied for vaccine design targeting multiple epitopes of the structural proteins of SARS-CoV-2 [72].
Recent advances towards natural plants as potential inhibitors of SARS-Cov-2 targets
Published in Pharmaceutical Biology, 2023
Zhouman He, Jia Yuan, Yuanwen Zhang, Runfeng Li, Meilan Mo, Yutao Wang, Huihui Ti
When the SARS-CoV-2 genome enters the cell, open reading frames are translated into nonstructural proteins (Nsps), forming a replicase complex. Among them, Nsp5, the main protease produced by SARS-CoV-2, also known as 3CLpro or Mpro, participates in the cleavage of polyproteins 1a and 1ab and is currently used as a target in drug development to inhibit viral replication (Jin Z et al. 2020). Mpro of SARS-CoV-2 is active in viruses and important for replication. A covalent bond was formed by cysteine-targeting covalent inhibitors, and binding to Cys145 in Mpro potentially inhibits virus replication (Paul et al. 2022). Therefore, a cysteine-targeting ligand facilitates the design of an effective lead drug for COVID-19 treatment. The three distinct substrates of PLpro, namely the viral polyprotein, degradative Lys48‐polyubiquitin, and antiviral ISG15 signals, all of which are crucial for inhibiting the virus and regulating the innate immune system. It was encouraging that high-throughput analyses uncovered that rac5c specifically inhibited SARS2 PLpro activity with an IC50 of 0.81 μM, suggesting that a PLpro inhibitor can target viral replication directly and efficiently (Klemm et al. 2020). Additionally, it has been found that tanshinones, which were isolated from Salvia miltiorrhiza, are specific and selective inhibitors for the SARS-CoV 3CLpro and PLpro (Park JY et al. 2012). Nsp12, which contains RdRp is a crucial protease for coronavirus replication and transcription and an important antiviral drug target (Wang MY et al. 2020) (Table 2).
Plant-Derived Natural Non-Nucleoside Analog Inhibitors (NNAIs) against RNA-Dependent RNA Polymerase Complex (nsp7/nsp8/nsp12) of SARS-CoV-2
Published in Journal of Dietary Supplements, 2023
Sreus A. G. Naidu, Ghulam Mustafa, Roger A. Clemens, A. Satyanarayan Naidu
The nsp12, also known as the RNA-dependent RNA-polymerase (RdRp), is the core component of SARS-CoV-2 RTC that operates replication and transcription of the viral RNA (17, 25, 26). The nsp12/RdRp has limited or no catalytic activity; however, when it forms a complex with specific viral proteins, a significant polymerase function is acquired (27, 28). Accordingly, the nsp12/RdRp forms a complex with two cofactors nsp7 and nsp8 for structure-functional support (29); nsp9, the dimer forming RNA-binding protein; nsp10, the cofactor in viral replication; and nsp14, the exoribonuclease (ExoN) (23, 29–31). The nsp14/ExoN serves as a CoV-specific intrinsic mechanism (absent in other RNA viruses) that effectively removes incorporated nucleoside analogs and restores the viral polymerase function [Neogi et al. 2020] (32). This proofreading ability of nsp14/ExoN is a setback for NA inhibitors such as remdesivir to block the RNA replication in SARS-CoV-2. Although the interaction between all these CoV-nsps is important for optimal replication of the viral RNA, the nsp7-nsp8-nsp12 complex constitutes the minimal core for RTC function (33). After host cell invasion, the viral genomic RNA serves as a template, and reprograms the host metabolism (including the protein synthesis machinery) to facilitate the translation of RdRp enzyme. Subsequently, the RdRp polymerizes a high quantity of nucleotides to support an uninterrupted viral replication.
Tapping the immunological imprints to design chimeric SARS-CoV-2 vaccine for elderly population
Published in International Reviews of Immunology, 2022
Asim Biswas, Rahul Shubhra Mandal, Suparna Chakraborty, George Maiti
Development of vaccine is time consuming and challenging especially for the mutating RNA viruses. However, the mutation rate of SARS-CoV-2 is lower than other single stranded RNA viruses like influenza or HIV [8]. RNA viruses have the tendency to lose infectivity after acquiring mutation but few quasi-species retain infectivity and others become highly infective. These highly infective species bypass the existing immunity to establish themselves in the circulation as a new variant. The repeated viral mutation is well observed during flu season caused by influenza viruses. Every year new flu vaccine is developed based on the previous year’s epidemiological data. SARS-CoV-2 rapid multiplication and infectivity allows the virus to acquire mutations such as D164G, A222V, L18F, P681H and N501Y mutations in the Spike (S) proteins, P323L in the NSP12 protein and R203K, G204R and A220V in the nucleocapsid proteins [9]. Current epidemiological studies have identified new variants in UK (B.1.1.7), South Africa (B.1.351) and Brazil (P.1) and all three have now been detected in the USA [10]. Current vaccines under use can neutralize emerging strains but to what extent they can protect elderly population remains a major concern.