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Viral infections
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
Sarah Elizabeth Blutt, Mary K. Estes, Satya Dandekar, Phillip D. Smith
Rotavirus virulence is related to properties of the proteins encoded by a subset of the 11 viral genes. Virulence is multigenic and associated with the products of genes 3, 4, 5, 9, and 10 (see Figure 28.1). The involvement of these genes in virulence is only partially understood. Gene 3 encodes the capping enzyme that affects levels of viral RNA replication and can antagonize innate immunity, and genes 4 and 9 encode the outer capsid proteins required to initiate infection. Gene 5 encodes a protein (NSP1) that functions as a major interferon antagonist and is discussed later (see “Rotavirus immunity”). Gene 10 codes for the nonstructural protein NSP4, which regulates calcium homeostasis and virus replication and functions as an enterotoxin.
Rotavirus
Published in Dongyou Liu, Handbook of Foodborne Diseases, 2018
Lijuan Yuan, Tammy Bui, Ashwin Ramesh
Upon delivery of the DLP, a viral transcription complex composed of VP1 and VP3 becomes transcriptionally active and begins synthesizing the 11 species of capped, nonpolyadenylated positive-sense strand mRNAs using the negative-sense RNAs [(−) RNA] of the dsRNA genome segments as templates.29 The RNA capping enzyme, found on the RNA exit tunnel, caps newly synthesized mRNA at the 5′ end before leaving the DLP. The structure of the VP1 tunnels allows for the chaperoning of the (−) RNA template back into the core, where it reassociates with the (+) RNA to reform the original genomic dsRNA.30 The capped mRNA transcripts perform two functions: to serve either for translation of virus-encoded proteins (early stages of the replication cycle); or to serve as the (+) RNA template for the synthesis of (−) RNA that is then incorporated into the genome of progeny viruses (late stages of the replication cycle).31 These capped mRNA transcripts are continuously synthesized by the transcription complexes, leading to the production of large amounts of viral mRNAs with the only determining factors being the availability of free nucleotides and ATP.30,32–34 mRNA exiting the DLP are immediately translated into the encoded proteins in the cytoplasm by host ribosomes.
Ribavirin
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
Emily Woolnough, Amanda Wade, Joe Sasadeusz
A fourth mechanism involves the prevention of capping of messenger RNA (mRNA) by ribavirin, resulting in inefficient translation of viral transcripts (Goswami et al., 1979). Early studies were performed using vaccinia virus and a variety of plant viruses (Lerch, 1987). Loss of cap structure has been demonstrated in ribavirin-treated cells that had been infected with equine infectious anemia virus as well as in ribavirin-treated cells infected with HIV (Fernandez-Larsson and Patterson, 1990). In vitro data suggest that ribavirin binds to eIF4E at the functional site used by 7-methylgua-nosine cap and selectively disrupts eIF4E organization, transport, and translation of mRNAs, therefore reducing the levels of oncogenes, such as cyclin D1 (Kentsis et al., 2004; Kentsis et al., 2005). An in vitro study demonstrated that ribavirin triphosphate (RTP) could bind to the NS5M mRNA 2′-O-methyl-transferase dengue virus and inhibit RNA cap methylation. IMPDH inhibition and the consequent decrease in intracellular GTP concentrations would favor RTP binding to the viral enzyme (Benarroch et al., 2004). Another in vitro study demonstrated that RTP can be used as a substrate by the vaccinia virus RNA capping enzyme and that when transferred to the RNA transcript, it precipitates inefficient translation (Bougie and Bisaillon, 2004). Other studies do not support interference with mRNA cap formation as a mechanism for antiviral activity (Browne, 1981; Rankin et al., 1989; Yan et al., 2005).
The discovery and development of mRNA vaccines for the prevention of SARS-CoV-2 infection
Published in Expert Opinion on Drug Discovery, 2023
Vivian Weiwen Xue, Sze Chuen Cesar Wong, Bo Li, William Chi Shing Cho
The COVID-19 mRNA vaccines offer different choices in the 5’ cap and 3’ tail structure. Currently, two main strategies are applied for capping during vaccine production. The first method is co-transcriptional capping, where one-third to half of the m7GpppG cap is incorporated in reverse orientation and cannot be transcribed. As a solution, anti-reverse cap analogs like (m27,3’-O)GpppG have been developed [43]. CleanCap® also provides a series of methylation-modified new-generation cap analogs that successfully achieve a 94% capping rate in IVT [44]. Various vaccines, such as BNT162b [45], ChulaCov19 [42], and mRNA vaccine candidates developed by Laczkó et al. [27], have chosen this type of optimized cap structure. For example, the IVT of BNT162b vaccines is achieved by T7 RNA polymerase by adding a trinucleotide cap1 analog ((m27,3’-O)Gppp(m2’-O)ApG) [45,46]. The second method for adding cap structures to therapeutic mRNA is through enzymatic catalysis, and vaccines including mRNA-1273 [40], SW0123 [34], and MRT5500 [47] utilize this capping strategy. For instance, in the IVT of mRNA-1273, a cap1 structure is added to the 5’ end through capping enzyme and 2’O-methyltransferase catalysis [40].
Recent progress in development of cyclin-dependent kinase 7 inhibitors for cancer therapy
Published in Expert Opinion on Investigational Drugs, 2021
Hanzhi Liang, Jintong Du, Reham M. Elhassan, Xuben Hou, Hao Fang
During transcription regulation, the CAK is a subunit of the universal transcription factor TFIIH. The role of CAK throughout all the RNA polymerase II (RNA Pol II) transcriptional cycle, from phosphorylation of the CTD, facilitates promoter clearance and arrest to the genome (Figure 1) [13–16]. CDK7 phosphorylates the CTD of RNA Pol II and enable it to enter the transcription process [13,17]. It also has been found that CDK7 promotes the recruitment of NELF and DSIF to RNA Pol II, resulting in a pause in transcription. During the pause, CDK7 mediated phosphorylation tether the capping enzyme to the 5ʹ- triphosphate end of the RNA transcript [13]. The 5ʹ- terminal of the mRNA will be processed, that is, the capping process. Meanwhile, CDK7 phosphorylation activated CDK9 and promoted the phosphorylation of DSIF, NELF, and RNA Pol II to end the pause and rapid extension of 5ʹcapped transcripts [13,14]. Inhibition of CDK7 resulted in a reduction of the phosphorylated level of CTD, weaken the pause in the proximal region of promoter, and hinder the capping process [18,19]. CDK2 and CDK13 can also be regulated by CDK7, which are related to late transcriptional events [20,21]. Besides, CDK7 is also involved in nucleotide excision repair, transcription of the HIV-1 genome, glucose consumption, and learning and memory [13–16,22,23].
New avenues for therapeutic discovery against West Nile virus
Published in Expert Opinion on Drug Discovery, 2020
Alessandro Sinigaglia, Elektra Peta, Silvia Riccetti, Luisa Barzon
Nucleoside analogues have been tested also as inhibitors of the MTase domain of WNV NS5 [125,126]. By virtual screening of compounds that putatively bind to the SAM-binding site of flavivirus MTase, compound NSC 12155 was identified as a broad-spectrum inhibitor, with strong activity against WNV and some activity against other flaviviruses [125]. The RNA capping activity of NS5 is a different druggable site in this domain. High-throughput screenings identified 2-thioxothiazolidin-4-ones as a class of inhibitors of capping enzyme GTP binding and GTase function of flavivirus NS5. Among candidates, the small-molecule BG-323 was successfully tested in vitro and in vivo as a broad anti-flavivirus molecule [127,128], though with no recent updates.