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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).
Regulation of C-Reactive Protein, Haptoglobin, and Hemopexin Gene Expression
Published in Andrzej Mackiewicz, Irving Kushner, Heinz Baumann, Acute Phase Proteins, 2020
Dipak P. Ramji, Riccardo Cortese, Gennaro Ciliberto
The carboxy-terminal DNA binding domain of IL-6DBP contains a heptad repeat of leucine residues (leucine zipper) preceded by clusters of basic amino acids. This is consistent with the observations that recombinant IL-6DBP binds DNA as a dimer.63 Interestingly, this C-terminal region of IL-6DBP is 96% identical to the corresponding region of C/EBP.63Upstream from this region, the two proteins show only 26% identity. The high degree of homology in the C-terminal DNA-binding domain suggested that IL-6DBP and C/EBP can form heterodimers with each other. To investigate this possibility, gel retardation experiments were performed with C/EBP and truncated IL-6DBP (containing only the DNA-binding domain) synthesized in vitro. While both C/EBP and truncated IL-6DBP generated a slower and faster migrating complex, respectively, a new retarded complex of intermediate mobility could be observed when the two proteins were either cotranslated or mixed after translation, indicating the formation of a heterodimer between the two polypeptide species (Figure 8). Similar results were obtained using truncated C/EBP and full-length IL-6DBP.63
Proto-Oncogene and Onco-Suppressor Gene Expression
Published in Enrique Pimentel, Handbook of Growth Factors, 2017
Multiple molecular interactions between the different Jun and Fos proteins, involving the formation of leucine zipper structures, occur in vivo and may have an important role in the regulation of gene expression by growth factors and other extracellular stimuli. Jun proteins function as transcription factors involved in the regulation of gene expression.196 A protein of 39 kDa associated in the form of a complex with the Fos protein within the nucleus of fibroblastic cells was identified as the product of the c-jun proto-oncogene.197 Fos and Jun proteins form a complex that binds to specific DNA sequences in the form of the transcription factor activator protein AP-1.198,199 Fos and Jun interact through respective motifs that constitute a heptad repeat of leucine residues, called the “leucine zipper”.200-203 Homodimers or heterodimers containing the Jun protein function as sequence-specific transcriptional activators.204-209 In addition to their positive action on gene transcription, the Jun and Fos proteins can act as negative regulators of the transcription of certain genes, such as the atrial natriuretic factor (ANF) gene.210 The effects of Fos and Jun on the expression of steroid hormone receptor genes can be either inhibitory or stimulatory and are receptor-, promoter-, and cell type-specific.211
Drugs repurposing for SARS-CoV-2: new insight of COVID-19 druggability
Published in Expert Review of Anti-infective Therapy, 2022
Sujit Kumar Debnath, Monalisha Debnath, Rohit Srivastava, Abdelwahab Omri
The primary target for vaccine development is the spike protein exposed on the surface and facilitates the attachment with the host’s ACE. There are two subunits of spike protein: S1 and S2. The S1 subunit tends to bind with the RBD on the host’s ACE. After that, the heptad repeat domain 1 and 2 (HR1 & HR2) on the S2 domain interacted with each other to produce a 6-helix bundle (6-HB) fusion core [56]. This fusion core further strengthens the virus fusion with the host cellular membrane. EK1 is an HR1 domain-targeted fusion inhibitor that was developed to inhibit viral cellular attachment. The fusion ability of SARS-CoV-2 was higher than other coronaviridae. The lipopeptide derivative of EK1 is EK1C4 which is another more potent fusion inhibitor. It inhibits the interaction between S-protein-mediated membrane fusion and pseudovirus with a low IC50 value. This compound is 150–250 times (approx.) more potent than the original EK1 peptide [56]. This compound also showed inhibitory activities against MERS-CoV, SARS-CoV and inhibited the replication of 5 live human CoVs. Salvianolic acid C was also demonstrated as an inhibitor of 6-HB.
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
Virus entry to the host cells is facilitated by transmembrane S glycoprotein, consisting of S1 and S2 subunits, which are responsible for binding to host cell and fusion between the viral envelop and cellular membranes of host [21]. Receptor-binding domain (RBD), present in S1 subunit, recognizes the angiotensin-converting enzyme 2 (ACE2) peptidase domain of host cell and initiates direct binding with it, while membrane fusion is attributed to the basic elements present in S2 subunit [22]. ACE2 are considered as the target receptors of SARS-CoV-2 [23]. After binding, the host protease cleaves and activates S proteins to allow the insertion of viral fusion peptide into the host cell membrane. After that, the three pairs of heptad repeat region (HR1 and HR2) interact leading to formation of a six-helix coiled bundle, which pulls the viral membrane towards that of the host cell, leading to their fusion. This results in the entry of viral genome into the host cell [24]. Presence of 5ʹ methylated cap and a 3ʹ polyadenylated tail in viral genome permits the attachment of RNA to the ribosome of host cells for translation. Replication of viral genome and transcription of the negative-sense sub-genomic mRNA are mediated by RNA polymerase [25]. Host ribosomes translate these RNAs into structural and accessory proteins in the endoplasmic reticulum. Protein–protein interactions required for virus assembly are initiated by M proteins, leading to the formation of progeny viruses which are released into the extracellular space through exocytosis [26].
Antimicrobial peptides and other peptide-like therapeutics as promising candidates to combat SARS-CoV-2
Published in Expert Review of Anti-infective Therapy, 2021
Masoumeh Sadat Mousavi Maleki, Mosayeb Rostamian, Hamid Madanchi
The entry of HIV-1 virus is remarkably similar to the entry of SARS-CoV2 virus into their target cells [89,90]. HIV-1 virus enters the host cell with two glycoprotein subunits on its surface, namely the gp120 subunit (equivalent to S1 of SARS-CoV-2) which is responsible for binding to the receptor, and the gp41 subunit (equivalent to S2 of SARS-CoV-2) which is responsible for fusion to the host cell membrane. Refolding of the N-terminal heptad repeat (NHR) and the C-terminal heptad repeat (CHR) of the gp41 subunit in the form of a 6 helixes bundle (6-HB), brings the virus and the cell membranes closer together, leading to a fusion reaction. NHR and CHR sequence-derived antiviral peptides, such as the FDA-approved drug T20 or Enfuvirtide, can competitively inhibit the formation of viral 6-HB, thereby inhibiting the fusion of the virus to the host cell membranes and ultimately inhibiting the virus entry [22,91]. Because HIV-1 gp41 protein is structurally and functionally similar to SARS-CoV2 protein S2, the question is whether Enfuvirtide can inhibit SARS-CoV2 entry into the cell as well. In an in silico study using molecular docking and molecular dynamic (MD), Calligari et al. suggest Enfuvirtide as a SARS-Cov2 inhibitor [92]. More researches on this FDA-approved drug and conducting clinical trials in this area could help develop drug discovery and treatment for COVID-19.