Abstract

The long term side effects of any newly introduced drug is a subject of intense research, and often raging controversies. One such example is the dipeptidyl peptidase-IV (DPP4) inhibitor used for treating type 2 diabetes, which is inconclusively implicated in increased susceptibility to acute pancreatitis. Previously, based on a computational analysis of the spatial and electrostatic properties of active site residues, we have demonstrated that phosphoinositide-specific phospholipase C (PI-PLC) from Bacillus cereus is a prolyl peptidase using in vivo experiments. In the current work, we first report the inhibition of the native activity of PI-PLC by two DPP4 inhibitors - vildagliptin (LAF-237) and K-579. While vildagliptin inhibited PI-PLC at micromolar concentrations, K-579 was a potent inhibitor even at nanomolar concentrations. Subsequently, we queried a comprehensive, non-redundant set of 5000 human proteins (50% similarity cutoff) with known structures using serine protease (SPASE) motifs derived from trypsin and DPP4. A pancreatic lipase and a gastric lipase are among the proteins that are identified as proteins having promiscuous SPASE scaffolds that could interact with DPP4 inhibitors. The presence of such scaffolds in human lipases is expected since they share the same catalytic mechanism with PI-PLC. However our methodology also detects other proteins, often with a completely different enzymatic mechanism, that have significantly congruent domains with the SPASE motifs. The reported elevated levels of serum lipase, although contested, could be rationalized by inhibition of lipases reported here. In an effort to further our understanding of the spatial and electrostatic basis of DPP4 inhibitors, we have also done a comprehensive analysis of all 76 known DPP4 structures liganded to inhibitors till date. Also, the methodology presented here can be easily adopted for other drugs, and provide the first line of filtering in the identification of pathways that might be inadvertently affected due to promiscuous scaffolds in proteins.

Highlights

  • Oral glucose elicits a greater insulin response than intravenous glucose infusion, a phenomenon known as the incretin effect1

  • The finding that the incretin effect is impaired in subjects with type 2 diabetes4 led to two major types of glucagon-like peptide-1 (GLP-1) based therapies5 - intravenously or sub-cutaneously administered GLP-1 mimetics that are resistant to DPP46, and the orally administered gliptins that prolong the physiological actions of incretin hormones by inhibiting DPP47–9

  • Due to the multifarious roles played by the DPP4 enzyme10–12, the possible side effects of these drugs are strongly contested by researchers who argue that current statistics are insufficient16,17 to conclusively attribute these side effects to the otherwise beneficial GLP-1 drugs18

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Summary

Introduction

Oral glucose elicits a greater insulin response than intravenous glucose infusion, a phenomenon known as the incretin effect1 This effect is mostly attributed to the intestinally derived hormones glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP). Due to the multifarious roles played by the DPP4 enzyme, the possible side effects of these drugs (acute pancreatitis, pancreatic cancer, etc.13–15) are strongly contested by researchers who argue that current statistics are insufficient to conclusively attribute these side effects to the otherwise beneficial GLP-1 drugs18 Compound promiscuity is another phenomenon that might play a crucial role in determining the side effects of these therapies, this aspect has rarely been pursued intensively

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