REVIEW | doi:10.20944/preprints202207.0300.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: poxviruses; Variola; smallpox; Monkeypox; Vaccinia; Orf; Molluscum; Tanapox
Online: 20 July 2022 (10:05:05 CEST)
Poxviridae have been successful pathogens throughout recorded history, infecting humans among a variety of other hosts. Although eradication of the notorious smallpox has been a globally successful healthcare phenomenon, the recent emergence of Monkeypox virus, also belonging to the Orthopoxvirus genus and causing human disease, albeit milder than smallpox, is a cause of significant public health concern. The ongoing outbreak of monkeypox, demonstrating human-human transmission, in previously non-endemic countries, calls for critical need into further research in the areas of viral biology, ecology and epidemiology to better understand, prevent and treat human infections. In the wake of these recent events, it becomes important to revisit poxviral infections, their pathogenesis and ability to cause infection across multiple non-human hosts and leap to a human host. The poxviruses that cause human diseases include Monkeypox virus, Molluscum contagiosum virus and Orf virus. In this review we summarize the current understanding of various poxviruses causing human diseases, provide insights into their replication and pathogenicity, disease progression and symptoms, preventive and treatment options and their importance in shaping modern medicine through application in gene therapy, oncolytic viral therapies for human cancers or as poxvirus vectors for vaccines.
ARTICLE | doi:10.20944/preprints202205.0393.v1
Subject: Life Sciences, Virology Keywords: poxviruses; protein kinase R; evolution; translational regulation; eIF2
Online: 30 May 2022 (10:42:41 CEST)
Crocodilepox virus (CRV) belongs to the Poxviridae family and mainly infects hatchling and juvenile Nile crocodiles. Most poxviruses encode inhibitors of the host antiviral protein kinase R (PKR), which is activated by viral double-stranded (ds) RNA formed during virus replication, resulting in the phosphorylation of eIF2 and subsequent shutdown of general mRNA translation. Because CRV lacks orthologs of known poxviral PKR inhibitors, we experimentally characterized one candidate (CRV157), which contains a predicted dsRNA-binding domain. Bioinformatic analyses indicated that CRV157 evolved independently from other poxvirus PKR inhibitors. CRV157 bound to dsRNA, co-localized with PKR in the cytosol, and inhibited PKR from various species. To analyze whether CRV157 could inhibit PKR in the context of a poxvirus infection, we constructed recombinant vaccinia virus strains that contain either CRV157 or a mutant CRV157 deficient in dsRNA binding in a strain that lacks PKR inhibitors. The presence of wild type CRV157 rescued vaccinia virus replication, while the CRV157 mutant did not. The ability of CRV157 to inhibit PKR correlated with virus replication and eIF2alpha phosphorylation. The independent evolution of CRV157 demonstrates that poxvirus PKR inhibitors evolved from a diverse set of ancestral genes in an example of convergent evolution.
ARTICLE | doi:10.20944/preprints202210.0302.v1
Subject: Life Sciences, Virology Keywords: poxviruses; monkeypox virus; envelope proteins; drug repurposing; bioactive phytochemicals; molecular docking, molecular simulation
Online: 20 October 2022 (09:32:02 CEST)
The monkeypox virus (MPXV) has become a major threat due to the increasing global caseload and the ongoing multi-country outbreak in non-endemic territories. Due to limited research in this avenue and the lack of intervention strategies, the present study was aimed to virtually screen bioactive phytochemicals against envelope proteins of MPXV via rigorous computational approaches. Molecular docking and molecular dynamic (MD) simulations were used to investigate the binding affinity of 12 phytochemicals against three envelope proteins of MPXV, viz., D13, A26, and H3. Silibinin, oleanolic acid, and ursolic acid were computationally identified as potential phytochemicals that showed strong binding affinity towards all the tested structural proteins of MPXV through molecular docking. The stability of the docked complexes was also confirmed by MD simulations. ADME analysis also computationally confirmed the drug-like properties of the phytochemicals, thereby asserting their suitability for consumption. Hence, this study envisions the candidature of bioactive phytochemicals as promising inhibitors against the MPXV, serving as template molecules that could further be experimentally evaluated for their efficacy against monkeypox.