Highly mutated SARS-CoV-2 is known aetiological factor for COVID-19. Here, we have demonstrated that the receptor binding domain (RBD) of the spike protein can interact with human dipeptidyl peptidase 4 (DPP4) to facilitate virus entry, in addition to the usual route of ACE2-RBD binding. Significant number of residues of RBD makes hydrogen bonds and hydrophobic interactions with alpha/beta-hydrolase domain of DPP4. With this observation, we created a strategy to combat COVID-19 by circumventing the catalytic activity of DPP4 using its inhibitors. Sitagliptin, linagliptin or in combination disavowed RBD to establish a heterodimer complex with both DPP4 and ACE2 which is requisite strategy for virus entry into the cells. Both gliptins not only impede DPP4 activity, but also prevent ACE2-RBD interaction, crucial for virus growth. Sitagliptin, and linagliptin alone or in combination have avidity to impede the growth of pan-SARS-CoV-2 variants including original SARS-CoV-2, alpha, beta, delta, and kappa in a dose dependent manner. However, these drugs were unable to alter enzymatic activity of PLpro and Mpro. We conclude that viruses hijack DPP4 for cell invasion via RBD binding. Impeding RBD interaction with both DPP4 and ACE2 selectively by sitagliptin and linagliptin is an potential strategy for efficiently preventing viral replication.
Title: The dipeptidyl peptidase 4 inhibitor linagliptin ameliorates renal injury and accelerated resolution in a rat model of crescentic nephritis Mayer AL, Scheitacker I, Ebert N, Klein T, Amann K, Daniel C Ref: British Journal of Pharmacology, 178:878, 2021 : PubMed
BACKGROUND AND PURPOSE: Dipeptidyl peptidase 4 (DPP-4) inhibitors are a class of oral glucose-lowering drugs used in the treatment of type 2 diabetes. In a pilot study using human kidney biopsies, we observed high DPP-4 expression in early crescent formation. This glomerular lesion occurs in different kidney diseases and is a hallmark in the pathogenesis of renal dysfunction. Therefore, we investigated the potential involvement of DPP-4 in the pathogenesis of nephritis induced by anti-glomerular basement membrane (GBM) antibody in rats. EXPERIMENTAL APPROACH: Linagliptin and vehicle were used to treat anti-GBM nephritis in a 2- and 8-week regimen, that is either preventive or therapeutic (treatment started 7 days or 4 weeks after disease induction). Kidney function, morphologic changes, inflammation and fibrosis were monitored. KEY RESULTS: In the long-term experiment, linagliptin preventive treatment in anti-GBM nephritic rats significantly reduced the number of crescents, glomerulosclerosis, tubular injury and renal fibrosis, compared with those in untreated nephritic rats. Both linagliptin regimes significantly lowered the number of Pax8+ cells on the glomerular tuft in anti-GBM nephritis, indicating accelerated resolution of the cellular crescents. The linagliptin treatment did not change the podocyte stress in both therapeutic groups. Therapeutic intervention with linagliptin resulted in weaker amelioration of renal disease on Week 8 than did preventive intervention. CONCLUSION AND IMPLICATIONS: DPP-4 inhibition with linagliptin ameliorates renal injury in a rat model of anti-GBM, indicating that linagliptin not only is a secure therapy in diabetes but also can improve resolution of glomerular injury and healing in non-diabetic renal disease.
Title: A Single Second Shell Amino Acid Determines Affinity and Kinetics of Linagliptin Binding to Type 4 Dipeptidyl Peptidase and Fibroblast Activation Protein Schnapp G, Hoevels Y, Bakker RA, Schreiner P, Klein T, Nar H Ref: ChemMedChem, 16:630, 2021 : PubMed
Drugs targeting type 4 dipeptidyl peptidase (DPP-4) are beneficial for glycemic control, whereas fibroblast activation protein alpha (FAP-alpha) is a potential target for cancer therapies. Unlike other gliptins, linagliptin displays FAP inhibition. We compared biophysical and structural characteristics of linagliptin binding to DPP-4 and FAP to better understand what differentiates linagliptin from other gliptins. Linagliptin exhibited high binding affinity (K(D) ) and a slow off-rate (k(off) ) when dissociating from DPP-4 (K(D) 6.6pM; k(off) 5.1x10(-5) s(-1) ), and weaker inhibitory potency to FAP (K(D) 301nM; k(off) >1s(-1) ). Co-structures of linagliptin with DPP-4 or FAP were similar except for one second shell amino acid difference: Asp663 (DPP-4) and Ala657 (FAP). pH dependence of enzymatic activities and binding of linagliptin for DPP-4 and FAP are dependent on this single amino acid difference. While linagliptin may not display any anticancer activity at therapeutic doses, our findings may guide future studies for the development of optimized inhibitors.
Title: Linagliptin, a DPP-4 inhibitor, ameliorates Abeta (1-42) peptides induced neurodegeneration and brain insulin resistance (BIR) via insulin receptor substrate-1 (IRS-1) in rat model of Alzheimer's disease Siddiqui N, Ali J, Parvez S, Zameer S, Najmi AK, Akhtar M Ref: Neuropharmacology, :108662, 2021 : PubMed
Alzheimer's disease (AD) is the most devastating neurodegenerative disorder, accounting over 46 million cases of dementia globally. Evidence supports that Brain Insulin Resistance (BIR) due to serine phosphorylation of Insulin Receptor Substrate-1 (IRS-1) has an association with AD. GLP-1 an incretin hormone, rapidly degraded by Dipeptidyl Peptidase-4 (DPP-4) has also confirmed its efficacious role in AD. Linagliptin, a DPP-4 inhibitor is hypothesized to increase GLP-1 level, which then crosses Blood Brain Barrier (BBB), decreases Amyloid-beta (Abeta) and insulin resistance in hippocampus. Thus, the present study was designed to evaluate Linagliptin in Abeta (1-42) peptides induced rat model of AD. Following 1 week of induction, rats were administered with Linagliptin (0.513mg/kg, 3mg/kg, and 5mg/kg) orally for 8 weeks and donepezil (5 mg/kg) as a reference standard. At the end of scheduled treatment neurobehavioral parameters were assessed. After this, rats were sacrificed, hippocampus was isolated from the whole brain for histopathological analysis and biochemical parameters estimation. Linagliptin dose-dependently and significantly reversed motor and cognitive impairment, assessed through locomotor activity (LA) and Morris water maze (MWM) test respectively. Moreover, Linagliptin augmented GLP-1 level and attenuated soluble Abeta (1-42), IRS-1 (s307), GSK-3beta, TNF-alpha, IL-1beta, IL-6, AchE and oxidative/nitrosative stress level in hippocampus. H&E and Congo red staining also exhibited neuroprotective and anti-amylodogenic effect respectively. Our study findings implies the significant effect of Linagliptin in reversing the behavioural and biochemical deficits by altering Abeta (1-42) and BIR via IRS-1 confirming one of the mechanism underlying the pathophysiology of AD.
A new chemical class of potent DPP-4 inhibitors structurally derived from the xanthine scaffold for the treatment of type 2 diabetes has been discovered and evaluated. Systematic structural variations have led to 1 (BI 1356), a highly potent, selective, long-acting, and orally active DPP-4 inhibitor that shows considerable blood glucose lowering in different animal species. 1 is currently undergoing clinical phase IIb trials and holds the potential for once-daily treatment of type 2 diabetics.
