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Computational Biology and Bioinformatics in Anti-SARS-CoV-2 Drug Development
Published in Debmalya Barh, Kenneth Lundstrom, COVID-19, 2022
Another interesting set of viral drug targets comprises viroporins, viral proteins capable of ion-channel formation. In SARS-CoV-2, such viroporins are the envelope protein E (ORF4a, which, being smallest of CoV structural proteins, is an integral membrane protein embedded in the envelope bilayer membrane), ORF3a (a 274-amino acid–long viral ion-channel protein involved in viral release, inflammasome activation, and cell death), and ORF8 (a cysteine-rich 29-amino acid single-passage transmembrane peptide), which are utilized by the virus to take control of the endoplasmic reticulum–Golgi complex intermediate compartment (ERGIC) [99]. Furthermore, the E and ORF3a proteins are highly promiscuous binders that can interact with more than 400 target proteins in infected host cells because of the presence of a PDZ-binding domain [99].
SARS-CoV-2 Morphology, Genomic Organisation and Lifecycle
Published in Srijan Goswami, Chiranjeeb Dey, COVID-19 and SARS-CoV-2, 2022
Srijan Goswami, Ushmita Gupta Bakshi
Envelope proteins or E-proteins are the smallest of all major structural proteins present on SARS-CoV-2. The major functions of the envelope protein are as follows:First, it helps in the assembly and release of viruses from host cells.Second, during the process of viral replication, it is largely located at the regions of intracellular trafficking, for example, near the endoplasmic reticulum and Golgi apparatus.It functions as a viroporin and self-assembles in host membranes forming pentameric protein-lipid pores that allow ion transport and plays a role in the induction of apoptosis (UniProtKB – P59637, n.d.).It is known to activate the host NLR family pyrin domain containing 3 (NLRP3) inflammasome, leading to interleukin-1 beta (IL-1β) overproduction.
Human Polyomavirus JC and Progressive Multifocal Leukoencephalopathy
Published in Sunit K. Singh, Daniel Růžek, Neuroviral Infections, 2013
Monica Mischitelli, Daniela Fioriti, Anna Bellizzi, Elena Anzivino, Fernanda Chiarini, Valeria Pietropaolo
Viral structural proteins are the three capsid proteins VP1, VP2, and VP3. In addition, there is the late protein named agnoprotein. VP1 is responsible for the icosahedral structure of JCV and contains the epitopes for antibody induction and recognition. VP2 and VP3 are minor structural components and they are necessary for JCV propagation (Weissert 2011). Agnoprotein directly interacts with TAg and contributes to the oncogenesis interfering with DNA repair and associating with several tumor suppressor proteins: the result is the uncontrolled cell proliferation (Del Valle and Khalili 2010). Finally, it has been demonstrated that agnoprotein acts as a viroporin (Suzuki et al. 2010).
The vital role of animal, marine, and microbial natural products against COVID-19
Published in Pharmaceutical Biology, 2022
Aljawharah A. Alqathama, Rizwan Ahmad, Ruba B. Alsaedi, Raghad A. Alghamdi, Ekram H. Abkar, Rola H. Alrehaly, Ashraf N. Abdalla
The E protein is an integral membrane protein (76–109 amino acids) with three distinctive domains, the N terminal, the hydrophobic, and the C terminal domains. As it is hydrophobic and forms viroporins, it mediates viral assembly on its release. Also, its heterotypical interaction with nsps, such as nsp2 and nsp3, is crucial curvature in the endoplasmic reticulum membrane. Its tail is partly embedded in the cytoplasm and targets the cis-Golgi complex region, while the N terminal has additional Golgi complex. The virion exits by the E protein when the ionic gradient is levels out in the endoplasmic reticulum Golgi intermediate compartment (ERGIC) and Golgi compartment. Thus, this protein has an essential role in viral pathogenesis, virion release and assembly (Satarker and Nampoothiri 2020).
An update on direct antiviral agents for the treatment of hepatitis C
Published in Expert Opinion on Pharmacotherapy, 2021
Carol Stanciu, Cristina Maria Muzica, Irina Girleanu, Camelia Cojocariu, Catalin Sfarti, Ana-Maria Singeap, Laura Huiban, Stefan Chiriac, Tudor Cuciureanu, Anca Trifan
All proteins that are indispensable for viral replication could represent new potential targets and the key to a fundamental strategy to prevent viral resistance. Combining inhibitors of different viral targets and host-related co-factors could block the development of multi-drug resistant strains. The most attractive future target is the small protein p7, which is implicated in different stages of the virus life cycle. This molecule was classified as viroporin because it has the ability to form ion channel structures. P7 inhibitors, such as N-carbamimidoyl-5-(1-methyl-1 H-pyrazol-4-yl)-2-naphthamide (BIT225), glycogen synthetase kinase 2 (GSK-2), and hexamethylamiloride (HMA) have been described [85–87]. BIT225 could represent a common treatment for HCV/HIV co-infected patients, because this molecule blocks p7 as well as some molecules involved in HIV replication. Host-targeting antivirals could also represent a potential target for HCV treatment. Furthermore, cyclophilin and miR-122 inhibitors have been identified as potential therapeutic targets.
Coronavirus disease 2019: investigational therapies in the prevention and treatment of hyperinflammation
Published in Expert Review of Clinical Immunology, 2020
Isabelle Amigues, Alexander H Pearlman, Aarat Patel, Pankti Reid, Philip C. Robinson, Rashmi Sinha, Alfred Hj Kim, Taryn Youngstein, Arundathi Jayatilleke, Maximilian Konig
Colchicine is a nonselective inhibitor of NLRP3 inflammasome that reduces the production of IL-1β [165]. The NLRP3 inflammasome is thought to play a role in the development of ARDS and acute lung injury and viroporin E, a protein expressed by SARS-CoV-1, was previously shown to activate the inflammasome [165–168] . In SARS-CoV-2, viroporin E is thought to play a major role in viral replication. The possibility of improving vascular inflammation and endothelial dysfunction has prompted 4 trials studying colchicine use in COVID-19 [168]. Two studies of colchicine use in COVID-19 have been reported; however, data on patients’ hyperinflammation status were not reported. In a randomized trial of 105 hospitalized patients with relatively mild COVID-19 infection, colchicine was given as a loading dose followed by 1 mg daily. Patients in the colchicine group had less risk of clinical deterioration (1.8% vs 14%) and better cumulative event-free 10-day survival rate (97% vs 83%) while there was no difference in CRP or troponin levels between the groups [169,170]. In the other series, 122 patients were given 1 mg daily, reduced to 0.5 mg daily for severe diarrhea (occured in 7.4%); the historical comparison standard of care group had 37% mortality while the colchicine group had 16% mortality [171]. However, 58% of the colchicine group received dexamethasone, compared to 32% of the historical comparison group. This limited evidence is not yet sufficient to support use of colchicine in COVID-19-CSS.