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Biology of Coronaviruses and Predicted Origin of SARS-CoV-2
Published in Debmalya Barh, Kenneth Lundstrom, COVID-19, 2022
Giorgio Palù, Alberto Reale, Nicolas G. Bazan, Pritam Kumar Panda, Vladimir N. Uversky, Murat Seyran, Alaa A. A. Aljabali, Samendra P. Sherchan, Gajendra Kumar Azad, Wagner Baetas-da-Cruz, Parise Adadi, Murtaza M. Tambuwala, Bruce D. Uhal, Kazuo Takayama, Ángel Serrano-Aroca, Tarek Mohamed Abd El-Aziz, Adam M. Brufsky, Kenneth Lundstrom
As with other viral proteins, one of the characteristic features of CoV proteins is their multifunctionality. This capability to execute multiple, diverse functions is determined by the capability of viral proteins to be engaged in a broad range of interactions with a multitude of viral and host partners, which, at least in part, can be explained by the presence of intrinsically disordered protein regions (IDPRs). In fact, three SARS-CoV-2 proteins, N, NSP8, and ORF6, are highly disordered, and the remaining proteins also contain functional IDPRs. For example, cleavage sites in the replicase 1ab polyprotein are found to be highly disordered, and almost all SARS-CoV-2 proteins contain molecular recognition features (MoRFs), which are the disorder-based protein–protein interaction sites that are capable of folding at interaction with specific partners, and are commonly utilized by proteins for target binding [40].
Exploration of Nanonutraceuticals in Neurodegenerative Diseases
Published in Raj K. Keservani, Anil K. Sharma, Rajesh K. Kesharwani, Nutraceuticals and Dietary Supplements, 2020
Swati Pund, Amita Joshi, Vandana Patravale
The number of therapeutic strategies based on blocking the effects of Aβ peptide is based on decreasing Aβ production by inhibition of β-secretase, inhibition of γ secretase, activation of α-secretase, inhibition of Aβ oligomerization or fibrillization and increasing Aβ degradation and clearance (Barage and Sonawane, 2015). Amyloid formation of a small intrinsically disordered protein; α-Synuclein is associated with PD (Bhasne and Mukhopadhyay, 2018; Stefanis, 2012). Counteracting intracellular and extracellular effects of α-Synuclein at the transcriptional and post-transcriptional level is an important therapeutic target in neurodegeneration. Inhibition of its aggregation or phosphorylation states, immunization or attenuation of its secretion and propagation offer additional therapeutic possibilities (Vekrellis and Stefanis, 2012). HD is a result of mutation in the IT-15 gene that expands abnormally the number of CAG nucleotide repeats causing expansions of glutamines (polyQ) (Arrasate and Finkbeiner, 2012). A triplet nucleotide repeat, cytosineadenonsine-guanine, is found near the 5′ end of the gene’s coding region and is translated into a polyQ stretch (Finkbeiner, 2011). N-terminal huntingtin peptides (Htt) with poly(Q) tracts in the pathological range (51–122 glutamines), form high molecular weight protein aggregates or misfolds with a fibrillar or ribbon-like structure suggesting amyloid fibrillogenesis in HD (Scherzinger et al., 1999). TATA-binding protein is also a potential candidate for interaction with huntington because of long polyglutamine stretch, ubiquitous expression, and nuclear localisation (Huang et al., 1998; van Roon-Mom et al., 2002).
COVID-19 during Pregnancy and Postpartum:
Published in Journal of Dietary Supplements, 2022
Sreus A. G. Naidu, Roger A. Clemens, Peter Pressman, Mehreen Zaigham, Kamran Kadkhoda, Kelvin J. A. Davies, A. Satyanarayan Naidu
Intrinsically Disordered Proteins (IDPs) are characterized by their biased amino acid composition and low sequence complexity with low content of bulky hydrophobic amino acids. Such protein sequences are unable to fold spontaneously into stable, well-defined globular 3-D structures. However, these sequences are dynamically disordered and fluctuate rapidly over a continuum of conformational space ranging from extended statistical coils to collapsed globules (Dyson and Wright 2005). Some proteins are entirely disordered, while others contain disordered sequences, referred to as IDRs, in combination with structured globular domains. IDPs function as hubs in protein interaction networks (Dunker et al. 2005). Furthermore, IDPs play a pivotal role in the ordered assembly of macro-molecular machines (i.e. ribosomes), in the organization of chromatin, in the assembly/disassembly of microfilaments and microtubules, in the transport through nuclear pore, in the binding and diffusion of small molecules, in the activity of protein and RNA chaperones as well as flexible “entropic” linkers to separate functional protein domains (Wright and Dyson 2015; Uversky 2019).
Phage display technology for target determination of small-molecule therapeutics: an update
Published in Expert Opinion on Drug Discovery, 2020
Yoichi Takakusagi, Kaori Takakusagi, Kengo Sakaguchi, Fumio Sugawara
Using PD technology will also be invaluable to identify druggable targets among intrinsically disordered proteins and regions (IDPs and IDPRs) [19], which cannot be elucidated by conventional approaches. Moreover, PD technology provides a better understanding of the molecular docking dynamics between a protein and small organic compound, similar to the allosteric regulation of proteins. PD technology will be involved in the identification and characterization of a new category of drugs such as iPSCs, anti-aging agents, oxygen modulators for radiosensitizing tumors, immunomodulators, and regulators of molecular metabolism. Together with the advancements in the understanding of biological aspects (e.g., evolution, development, and differentiation) and the identification of drug candidates in nature (inspired by traditional medicine), the use of PD will enable the next generation drug R&D.
Discovery of drugs that directly target the intrinsically disordered region of the androgen receptor
Published in Expert Opinion on Drug Discovery, 2020
Intrinsically disordered proteins (IDPs) or regions (IDRs) lack a stable structure in isolation. This property of structural plasticity permits an IDP/R to exist as multiple and changing conformations that vary depending upon its interacting binding partners and/or the protein’s environment. The lack of a stable binding site together with presumed flat large protein–protein interaction areas reflects the challenges in developing drugs to these targets and contrast with the long-term success of drug development to folded proteins with three-dimensional structures that are set in the ‘lock-and-key’ model. Uncertainties to the feasibility of achieving specificity with small molecule inhibitors or activators and the laborious drug discovery approaches needed are probably the main reasons that only two drugs that directly bind to an IDP/IDR have reached clinical trials (ClinicalTrials.gov Identifiers: NCT02606123 and NCT00509132).