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Order Bunyavirales
Published in Paul Pumpens, Peter Pushko, Philippe Le Mercier, Virus-Like Particles, 2022
Paul Pumpens, Peter Pushko, Philippe Le Mercier
The comprehension of general mechanisms of arenaviral self-assembly and the ways to involve arenaviruses in the VLP methodology evolved with understanding of the role played by the protein Z of LASV and LCMV and its ability to self-assemble in vitro (Kentsis et al. 2002) and in mammalian cells (Perez et al. 2003; Strecker et al. 2003). In fact, the small RING finger protein Z acts as a matrix protein that is a driving force for the viral assembly and budding. The protein Z self-assembles in the absence of any other viral proteins and is sufficient for the release of enveloped protein Z-based VLPs (for a review, see Urata and Yasuda 2012). Although protein Z demonstrates strong variability among different arenaviral species, all arenaviruses encode and use it to initialize self-assembly.
Omics and coagulation disorders in pregnancy
Published in Moshe Hod, Vincenzo Berghella, Mary E. D'Alton, Gian Carlo Di Renzo, Eduard Gratacós, Vassilios Fanos, New Technologies and Perinatal Medicine, 2019
Sara Ornaghi, Michael J. Paidas
The multifactorial etiology of VTE greatly limits the clinical value of genetic analysis due to the presence of several confounding variables, i.e., different processes regulating protein expression and gene-to-gene interactions, which result in a wide range of variability in the link between genotype and phenotype (16). In addition, diagnosis of VTE is still challenging because of the lack of suitable biological assays with sufficient specificity and positive predictive value. In this context, proteomic technology has gained growing attention in the analysis of cellular and plasma components involved in thrombosis and hemostasis, and several biomarkers have been identified with the ability to discriminate VTE cases from healthy controls in pilot studies (17). However, independent clinical validation of these newly identified potential VTE biomarkers is still lacking, thus making the road to their routine clinical application for diagnosis and risk stratification long. Anyhow, the use of an integrated omic approach has the potential to provide substantial data in the quest for VTE biomarker and therapeutic target discovery, thus highlighting the importance of establishing multidisciplinary collaboration between clinicians and omic experts. This importance has been proved in a recently published case-control study in which advanced proteomic techniques were used to assess blood samples collected from 200 individuals before occurrence of VTE (18). Two proteins, transthyretin (a vitamin K–dependent protein Z) and protein/nucleic acid deglycase DJ-1, were identified as the strongest predictive biomarker candidates, supporting their further investigation in larger clinical studies (19).
Personalizing liver targeted treatments and transplantation for patients with alpha-1 antitrypsin deficiency
Published in Expert Review of Precision Medicine and Drug Development, 2021
Anita Pye, Sheeba Khan, Tony Whitehouse, Alice M Turner
An oral small molecule corrector is currently being developed by the biopharmaceutical company Vertex Pharmaceuticals. This family of protein correctors aims to address the underlying cause of AATD by facilitating proper folding of the Z-allele protein (Z-AAT) and thus preventing intracellular protein polymerization and increasing secretion of functionally active protein [11]. The corrector therapy is designed to restore the body’s ability to produce its own AAT, increasing production as needed and has the potential to treat both lung and liver manifestations of AATD. There is currently limited data in the public domain around this molecule but Vertex report that Phase 1 evaluation of single and multiple ascending doses of VX-814 has been completed and has now advanced into the next stage of development. The Phase 2 study of VX-814 is designed to assess the change in plasma levels of functional AAT and its safety and tolerability in AATD (NCT04167345). A total of 50 Pi*ZZ subjects will be randomized to active drug or placebo and clinical data is anticipated in late 2020. However, a recent press release reported that Vertex are discontinuing further development of the VX-814 molecule due to liver enzyme elevations seen in patients across different doses meaning that it would not be feasible to safely reach targeted exposure levels. Vertex has also advanced a second molecule, VX-864, into Phase 1/2 development though whether it will be possible to fully correct AAT levels remains unclear.
Genetic risk factors for venous thromboembolism
Published in Expert Review of Hematology, 2020
Bengt Zöller, Peter J. Svensson, Björn Dahlbäck, Christina Lind-Hallden, Christer Hallden, Johan Elf
Anticoagulation and coagulation genes are natural candidate genes for VTE. For instance, several genetic variants have been found among VTE patients in the THBD gene [65]. Some of these THBD genetic variants also exhibit reduced functional activity [65]. Still, the THBD gene remains to be formally linked to VTE [43,44]. A Ser219Gly missense variant in the endothelial protein C receptor (EPCR), i.e. PROCR gene, has been linked to VTE [66]. This has been confirmed in the GWAS study by Lindstrom et al [43]. Many other genes involved in the regulation of the coagulation system has not been genetically linked to VTE such as tissue factor pathway inhibitor (TFPI), Heparin cofactor II (SERPIND1), protein Z (PROZ), and genes involved in the fibrinolytic system.
Antibacterial activity of 3-methylbenzo[d]thiazol-methylquinolinium derivatives and study of their action mechanism
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2018
Ning Sun, Ruo-Lan Du, Yuan-Yuan Zheng, Qi Guo, Sen-Yuan Cai, Zhi-Hua Liu, Zhi-Yuan Fang, Wen-Chang Yuan, Ting Liu, Xiao-Mei Li, Yu-Jing Lu, Kwok-Yin Wong
Bacterial cell division is an essential process that has not yet been targeted by clinically approved antibiotics and thus it is a very important research area for antibacterial discovery. Bacterial cell division is believed to be critical in new antibiotic development because it is an essential process for bacterial survival and the bacterial divisome possesses a complex set of biochemical machinery that contains many proteins. The most important division proteins are widely conserved among bacterial pathogens and they are almost absent in eukaryotic cells6. Among these proteins, filamentous temperature sensitive protein Z (FtsZ) plays a critical role in cell division process. To initiate cell division, FtsZ assembles into protofilaments in a GTP dependent manner and forms a ring-like structure (Z-ring) at the division site7,8. Z-ring functions as a scaffold for the assembly of other cell division proteins to form bacterial divisome. Although the composition and the interdependency of divisome members may vary among different species, most bacteria depend on FtsZ as the central pacemaker protein9. Therefore, FtsZ is an attractive target for the development of novel antimicrobials.