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Emergence and Pathogenesis of Avian Influenza in Humans
Published in Sunit K. Singh, Human Respiratory Viral Infections, 2014
Jennifer R. Plourde, Kevin S. Harrod
Influenza RdRp replicates the viral genome and transcribes viral mRNA encoding proteins. Through a process known as “cap-snatching,” a 5′ capped primer is taken from host pre-mRNA transcripts and used to initiate mRNA synthesis.63,64 The same polymerase used for transcription is used for polyadenylation of the mRNA transcripts. A stretch of five to seven uracil residues and an adjacent double-stranded region of the viral RNA promoter are required for polyadenylation.65–67 In addition to translation of eight influenza proteins from the eight mRNAs generated through transcription, the translation of M and NS mRNA can result in two proteins due to splicing (such as M1 and M2, and NS1 and NEP/NS2, respectively).32
What are the considerations when selecting a model for influenza drug discovery?
Published in Expert Opinion on Drug Discovery, 2023
Woo-Jin Shin, Seongil Choi, Baik-Lin Seong
As mentioned in the ‘Drug Discovery Strategies’ section, with the aid of in silico pharmacophore-based drug discovery, target-based drug discovery has the potential to reduce time and cost during the hit identification process. The unique ‘cap-snatching’ mechanism of influenza viruses and other sNSVs offers attractive antiviral targets, such as the viral cap-binding domain and viral endonuclease. Currently, there are several investigative drugs that inhibit influenza virus replication and which have the potential to reduce clinical symptoms. Notably, ZSP1273, an anti-influenza small-molecule drug that targets the PB2 cap-binding domain, shows antiviral activity higher than that of pimodivir (a first-in-class influenza PB2 inhibitor) under similar experimental conditions. Furthermore, the report of this drug demonstrates that the efficacy of the delayed treatment of ZSP1273 was higher than that of oseltamivir all the while having no adverse side-effects [22]. We also note that, as an alternative to the replication step, the viral entry step can also be an attractive antiviral target. It is also of interest that type II transmembrane serine proteases (TTSPs) are currently being investigated in a clinical setting for their role in the proteolytic cleavage of the HA protein, which is critical for the fusion of the viral membrane with the cellular endosomal membrane [23]. So far, three TTSPs (HAT, TMPRSS2, TMPRSS4) were reported to be involved in proteolytic cleavage, and TTSP knockout mice have shown a significant reduction in lung pathology as well as body weight loss and mortality.
Searching for effective antiviral small molecules against influenza A virus: A patent review
Published in Expert Opinion on Therapeutic Patents, 2021
Tiziana Ginex, F. Javier Luque
Efforts targeting the RNA synthesis have primarily involved nucleoside analogs, such as favipiravir, which acts as a purine mimic that inhibits the polymerase activity in a broad range of influenza virus, including strains resistant to amantadine and oseltamivir [105]. In the cap-snatching process, the viral polymerase uses its PB2 cap-binding domain to capture the 5′-cap of nascent host capped RNAs, the PA endonuclease domain cleaves the capped RNA 8–14 nucleotides downstream of the cap structure, and the capped RNA fragments are then used as primers to initiate transcription of viral mRNAs. Drug discovery studies led to the development of pimodivir (VX-787), which blocks the PB2 activity (Kd of 24 nM) of the viral polymerase, being active against a diverse panel of influenza A virus strains, including H1N1pdm09 and H5N1 strains [106]. On the other hand, baloxavir marboxil (Figure 5) inhibits the endonuclease activity within the polymerase PA subunit (IC50 of 2.5 nM in an enzymatic assay of the endonuclease activity) [107]. Baloxavir acid potently and selectively inhibits the PA domain of influenza A and B viruses, without affecting the RdRp activity of PB1 or cap-binding activity of PB2. Nevertheless, treatment resistance has been associated with the occurrence of mutation I38T (and at less extent I38M and I38F) that reduces the susceptibility to the drug [108].
Investigational antiviral therapies for the treatment of influenza
Published in Expert Opinion on Investigational Drugs, 2019
Jie Yang, Yingna Huang, Shuwen Liu
PA subunit is mainly composed of the N-terminal domain and C-terminal domain. In 2009, both Yuan and Dias revealed the crystal structure and function of PAn [51,52]. In order to carry out the progress of ‘cap-snatching’, PAn needs to cleave host 10–13 nucleotides fragments as primes to initiate viral mRNA synthesis [53]. There are no similar events and corresponding enzymes in the host cells. Therefore, influenza PAn endonuclease inhibitors can selectively block endonuclease activity in viral transcription initiation without affecting the host cells [54]. Additionally, the C-terminal domain of PA (PAc) containing a hydrophobic groove is considered to combine with PB1 for complex formation and transportation to the nucleus. Thus, the critical role of PA and high sequence conservation suggest that it is a potential target to discover new drugs.