Correction: Jain et al. Proteomic Approach for Comparative Analysis of the Spike Protein of SARS-CoV-2 Omicron (B.1.1.529) Variant and Other Pango Lineages. Proteomes 2022, 10, 34.

In the publication [...].

Proteomic Approach for Comparative Analysis of the Spike Protein of SARS-CoV-2 Omicron (B.1.1.529) Variant and Other Pango Lineages.

The novel SARS-CoV-2 variant, Omicron (B.1.1.529), is being testified, and the WHO has characterized Omicron as a variant of concern due to its higher transmissibility and very contagious behavior, immunization breakthrough cases. Here, the comparative proteomic study has been conducted on spike-protein, hACE2 of five lineages (α, ß, δ, γ and Omicron. The docking was performed on spike protein- hACE-2 protein using HADDOCK, and PRODIGY was used to analyze the binding energy affinity using a reduced Haddock score. Followed by superimposition in different variant-based protein structures and calculated the esteem root mean square deviation (RMSD). This study reveals that Omicron was seen generating a monophyletic clade. Further, as α variant is the principal advanced strain after Wuhan SARS-CoV-2, and that is the reason it was showing the least likeness rate with the Omicron and connoting Omicron has developed of late with the extreme number of mutations. α variant has shown the highest binding affinity with hACE2, followed by ß strain, and followed with γ. Omicron showed a penultimate binding relationship, while the δ variant was seen as having the least binding affinity. This proteomic basis in silico analysis of variable spike proteins of variants will impart light on the development of vaccines and the identification of mutations occurring in the upcoming variants.

A novel GLP-1/GIP dual receptor agonist protects from 6-OHDA lesion in a rat model of Parkinson's disease.

The incretins glucagon-like peptide 1 (GLP-1) and glucose dependent insulinotropic polypeptide (GIP) are growth factors that have shown neuroprotective effects in animal models of Parkinson's and Alzheimer's disease. In addition, the GLP-1 mimetic exendin-4 has shown protective effects in a clinical trial in Parkinson's disease (PD) patients. GLP-1 analogues are currently on the market as treatments for type II diabetes. We previously showed that the novel dual agonist (DA-JC1) was effective in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. Here we demonstrate that DA-JC1 is neuroprotective in the 6-OHDA brain lesion rat model of PD. When treating rats for 6 weeks with DA-JC1 at 25 nmol/kg ip once-daily, motor activity as tested in the Rotarod and in the open field was much improved. In the amphetamine and apomorphine circling behaviour tests, the 6-OHDA induced impairments were much reduced by the DA-JC1 treatment. The number of TH positive dopaminergic neurons in the substantia nigra was decreased by 6-OHDA lesion and was increased by DA-JC1 treatment. Dopamine levels in the basal ganglia were reduced by 6-OHDA lesion and increased by DA-JC1. In western blot analysis, levels of the growth factor GDNF and pAkt/CREB cell signaling was enhanced by DA-JC1. The autophagy marker Beclin1 was also activated by the drug. The results demonstrate that dual GLP-1/GIP receptor agonists show promise as a novel treatment for PD.

Novel incretin analogues improve autophagy and protect from mitochondrial stress induced by rotenone in SH-SY5Y cells.

Currently, there is no viable treatment available for Parkinson's disease (PD) that stops or reverses disease progression. Interestingly, studies testing the glucagon-like-peptide-1 (GLP-1) mimetic Exendin-4 have shown neuroprotective/neurorestorative properties in pre-clinical tests and in a pilot clinical study of PD. Incretin analogues were originally developed to treat type 2 diabetes and several are currently on the market. In this study, we tested novel incretin analogues on the dopaminergic SH-SY5Y neuroblastoma cells against a toxic mitochondrial complex I inhibitor, Rotenone. Here, we investigate for the first time the effects of six different incretin receptor agonists - Liraglutide, D-Ser2-Oxyntomodulin, a GLP-1/GIP Dual receptor agonist, dAla(2)-GIP-GluPal, Val(8)GLP-1-GluPal and exendin-4. Post-treatment with doses of 1, 10 or 100 nM of incretin analogues for 12 h increased the survival of SH-SY5Y cells treated with 1 µM Rotenone for 12 h. Furthermore, we studied the post-treatment effect of 100 nM incretin analogues against 1 µM Rotenone stress on apoptosis, mitochondrial stress and autophagy markers. We found significant protective effects of the analogues against Rotenone stress on cell survival and on mitochondrial and autophagy-associated markers. The novel GLP-1/GIP Dual receptor agonist was superior and effective at a tenfold lower concentration compared to the other analogues. Using the Phosphatidylinositol 3-kinase (PI3K) inhibitor, LY294002, we further show that the neuroprotective effects are partially PI3K-independent. Our data suggest that the neuroprotective properties exhibited by incretin analogues against Rotenone stress involve enhanced autophagy, increased Akt-mediated cell survival and amelioration of mitochondrial dysfunction. These mechanisms can explain the neuroprotective effects of incretin analogues reported in clinical trials. GLP-1, GIP and dual incretin receptor agonists showed protective effects in SH-SY5Y cells treated with the stressor Rotenone. The novel GLP-1/GIP dual receptor agonist was superior and effective at a tenfold lower concentration compared to the other analogues. The drugs protected the cells from rotenone-induced impairment in cell growth and Akt activation, mitochondrial damage, impairments of autophagy and apoptotic cell signalling. See paper for details.