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Emerging Nanotechnology-Enabled Approaches to Mitigate COVID-19 Pandemic
Published in Devarajan Thangadurai, Saher Islam, Charles Oluwaseun Adetunji, Viral and Antiviral Nanomaterials, 2022
Maria Shoukat, Samiullah Khan, Arshad Islam, Maleeha Azam, Malik Badshah
Recent studies demonstrated the role of AuNPs to inhibit the cell-entry mechanism of MERS-CoV. The S2 protein of MERS-CoV is much similar to SARS-CoV-2 S2 containing heptad repeat 1 (HR1), heptad repeat 2 (HR2), and a fusion protein (FP). As showed in Figure 13.3, once the FP binds with the cell membrane of the host cell, HR1 and HR2 combine to form a six-helix bundle by binding together (6-HB). The six-helix bundle pulls together the host cell membrane and viral envelope supporting fusion. A peptide, named pregnancy-induced hypertension (PIH), has been identified with similar conformation as of HR2. This peptide can bind with HR1 to inhibit the development of 6-HB, preventing the cell-fusion process. The efficiency of PIH was further increased by immobilising it on the gold nanorods (PIH−AuNRs), resulting in a 10-fold increase in inhibitory affects and complete blockage of cell fusion. The PIH−AuNRs also depict high biocompatibility (Huang et al. 2019).
Order Nidovirales
Published in Paul Pumpens, Peter Pushko, Philippe Le Mercier, Virus-Like Particles, 2022
Paul Pumpens, Peter Pushko, Philippe Le Mercier
Gao et al. (2013) performed the thorough 3D examination of the so-called fusion core of the MERS-CoV. As known, the heptad repeats HR1 and HR2 of the S protein assemble into a complex called the fusion core, which represents a key membrane fusion architecture. The HR sequences were variably truncated, then connected with a flexible aa linker and produced in E. coli. The recombinant protein automatically assembled into a trimer in solution, displaying a typical α-helical structure. One of these trimers was crystallized, and its structure was solved at a resolution of 1.9 Å. A canonical 6-helix bundle, like those reported for other coronaviruses, was revealed, with three HR1 helices forming the central coiled-coil core and three HR2 chains surrounding the core in the HR1 side grooves. Moreover, the complex structure of the receptor binding domain in the MERS-CoV protein S1 bound to its receptor CD26, also known as dipeptidyl peptidase 4 (DPP4), has been successfully solved by the same team (Lu G et al. 2013).
Homeostasis of Dopamine
Published in Nira Ben-Jonathan, Dopamine, 2020
The SNARE complex is formed by members of the synaptosomal-associated protein 25 (SNAP-25), vesicle-associated membrane protein (VAMP) and members of the syntaxins family. Interactions between these proteins create a four-helix bundle, formed by two helices of SNAP-25, one vesicular-transmembrane VAMP and one presynaptic plasma membrane syntaxin that brings together the vesicular and plasmatic membranes. Other proteins that interact with the SNARE complex include Munc-18, complexin, synaptophysin, and synaptotagmin [77]. In addition, synaptotagmin serves as a calcium sensor and regulates the SNARE zipping. The SM proteins are evolutionary conserved cytosolic proteins that serve as essential partners for SNARE proteins in fusion. Among these is Munc 18, which primarily interacts with syntaxin-1 and whose function is tightly regulated by calcium.
A PDGFRB- and CD40-targeting bispecific AffiMab induces stroma-targeted immune cell activation
Published in mAbs, 2023
Alessandro Mega, Aman Mebrahtu, Gustav Aniander, Eva Ryer, Annette Sköld, Anna Sandegren, Eva Backström Rydin, Johan Rockberg, Arne Östman, Fredrik Y. Frejd
Affibody molecules are small (6.5 kDa) and very stable affinity proteins based on a three-helix bundle domain. Through combinatorial protein engineering, Affibody molecules can be selected with the ability to bind any given target.25 Their small size, lack of disulfide bonds and robustness of the molecules make them ideal tools for tumor targeting26 and as fusion partners with monoclonal antibodies (mAbs) to create multispecific antibody-based affinity proteins, denoted AffiMabs.27 Clinical utility of Affibody molecules has been demonstrated both for tumor targeting in patients with metastatic breast cancer,28 as well as for chronic treatment of inflammatory disorders with data of well-tolerated and efficacious treatment of patients with plaque psoriasis up to three years.29 An Affibody molecule is available for binding to PDGFRB, named ZPDGFRb_3,30 and has been shown in imaging studies to target PDGFRB-expressing remodeling tumor stroma in syngeneic tumors and in xenografts of glioma (U87) in vivo.30,31
Advances with the discovery and development of novel sigma 1 receptor antagonists for the management of pain
Published in Expert Opinion on Drug Discovery, 2023
Mallory Burns, Nicholas Guadagnoli, Christopher R. McCurdy
The S2R receptor is smaller than S1R, at a molecular weight of 18–22 kDa. The crystal structure shows the receptor is a closely associated homodimer and confirmed the expected four-helix bundle folding [49]. Unlike S1R, the function of dimerization of S2R remains unknown and appears unaffected by ligand binding. Despite S1R and S2R not being homologues and not sharing the same folding, the binding pockets are quite similar. The cocrystal structure with highly S2R selective ligand Z4857158944 shows several important residues within the binding pocket. In S2R, Asp56 bridges the extracellular loop 1 to TM4 through hydrogen bonds and is likely indicated in receptor folding and indirectly in ligand recognition. Asp29 and Glu73 are also acidic residues able to form a salt bridge with ionizable ligands, as shown in Figure 3. The binding site is deeply occluded and surrounded by many hydrophobic and aromatic residues, much like the S1R binding site [49]. With the crystal structure solved, structure-based drug design can help to produce S2R or S1R selective ligands.
Antimicrobial peptides: A plausible approach for COVID-19 treatment
Published in Expert Opinion on Drug Discovery, 2022
Pooja Rani, Bhupinder Kapoor, Monica Gulati, Atanas G. Atanasov, Qushmua Alzahrani, Reena Gupta
The six-helix bundle created by interaction of HR1 with HR2, responsible for getting both viral and host cell membranes in each other<apos;>s vicinity for fusion, is another significant target for the development of antiviral drugs [54]. Certain lipopeptides obtained from EK1, a pan-coronavirus fusion inhibitor effective against five HCoVs, including SARS-CoV, MERS-CoV, and three SARS-related CoVs, were synthesized employing covalent attachment to cholesterol or palmitic acid using polyethylene glycol as a spacer to give corresponding lipopeptides EK1C and EK1P, respectively. These two peptides inhibited SARS-CoV2 mediated cell–cell fusion indicating that lipidation, especially cholesterol-modification is an attractive approach. To explore further, Xia et al. synthesized a number of derivatives of EK1C using multiple linkers containing 3–5 glycine/serine amino acid residues and polyethylene glycol-based spacer with variable arm length. Among the synthesized derivatives, EK1C4 containing GSGSG linker and PEG4 spacer was reported to be the most potent fusion inhibitor. The in vivo study in murine model also indicated the protective effect of EK1C4 against HCoV-OC43 infection, indicating its potential in prophylaxis as well as treatment of SARS-CoV-2 infection [55].