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Sitagliptin (Januvia), (1x70)

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Contents

Structural Highlights

Januvia is an aromatic compound with a terminal polar and a . The enzyme DPP-4 consists of a and other . Residues of importance for binding purposes between the enzyme DPP-4 and Januvia include the (Ser630, His740, and Asp708) and two glutamates (Glu205 and Glu206).[1]

Function

Sitagliptin, more commonly known as Januvia, is a member of a class called dipeptidyl peptidase 4 (DPP-4) inhibitors, which has been approved for the therapy of type 2 diabetes.[2][3] Januvia is highly potent and a .[3] DPP-4 is an membrane-associated exopeptidase which plays a vital role in glucose metabolism. Januvia and other DPP-4 inhibitors allow the effects caused by the enzyme DPP-4 to be counteracted, thereby stimulating an increase in insulin secretion when hyperglycemia is present and inhibiting glucagon secretion.[2] These changes in insulin and glucagon levels can lead to lower haemoglobin A1c (HbA1c), fasting, and postprandial glucose concentrations, which alleviates many complications for individuals affected by type 2 diabetes with hyperglycaemia.[3]

Mechanism of Action

Incretin hormones, Glucagon-like peptide-1 (GLP-1) and Glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day and levels are increased in response to a meal.[3] When blood glucose concentrations rise above normal levels, GLP-1 and GIP increase insulin secretion and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. In addition, GLP-1 also plays an important role reducing glucagon secretion from pancreatic alpha cells, delaying gastric emptying, and potential induction of satiety.[2] The activity of GLP-1 and GIP is limited by the enzyme Dipeptidyl Peptidase-4 (DPP-4).[3] DPP-4 is an antigenic membrane serine exopeptidase that cleaves proline dipeptides from the N-terminal end of GLP-1 and GIP, rapidly hydrolyzing GLP-1 and GIP to produce inactive products. Januvia (Sitagliptin) is a , which prevents the enzymatic hydrolysis of GLP-1 and GIP by DPP-4.[3] Thus, concentrations of the active forms of these incretin hormones are increased, which in turn increase insulin release and decrease glucagon levels by the pancreas in a glucose-dependent manner. Ultimately, these levels of insulin and glucagon result in a decrease in blood glucose levels. In individuals with type 2 diabetes, this lowering or normalization of blood glucose levels can be essential in alleviating major complications and improving overall quality of life. Januvia inhibits DPP-4 by binding to the , which consists of a and other . Januvia situates its trifluorophenyl group within the S1 hydrophobic pocket, forming four hydrogen bond interactions with the residues Glu 205, Glu 206, and Tyr 662, and burying its trifluoro group within a tight pocket formed by residues Ser 209 and Arg 358.[4]

Januvia Bound to DPP-4

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Agonistic Effects

The incretin hormones GLP-1 and GIP are released by the intestine and signal the synthesis and release of insulin from pancreatic beta-cells.[2] Type 2 diabetes has been correlated to a progressive decline in beta-cell numbers and function, leading to insulin deficiency. DPP-4 inhibitors, such as Januvia, increase levels of active GLP-1 after a meal and reduces the glycemic parameters HbA1c, and fasting and postprandial glucose concentrations. Higher levels of GLP-1 have been shown to promote beta-cell proliferation and reduce the chance of beta-cell death.[5] The preservation, neogenesis, or restoration of beta-cell function is vital in altering the progression of defective insulin secretions. Current research suggests Januvia and other DPP-4 inhibitors not only sustain glycaemic control, but are also potentially involved in tissue repair, anti-inflammatory mechanisms, and the enhancement of immunotherapy in cancer treatment.[6]

Prolonged Treatment

Prolonged treatment of DPP-4 inhibitors has been linked to an increased risk in hypoglycaemia, weight gain, as well as gastrointestinal side effects. DPP-4 inhibitors, prescribed to stabilize incretin hormones, also extend the action of hormones peptide YY, growth hormone-releasing hormone, neuropeptide Y, substance P and several chemokines. Prolonged exposure to these hormones may increase the risk of high blood pressure, neurogenic inflammation and allergic reactions.[5]

Possible Disease in Humans

Januvia has been linked to rheumatoid arthritis and various acute and chronic inflammatory diseases.[6] Psoriasiform, an autoimmune skin inflammation, has also been observed in patients taking Januvia. Januvia can lead to low blood sugar, especially when used in conjunction with other medications that cause low blood sugar.[7] Common side effects involving Januvia include upper-respiratory infections, sore throat, and a stuffy or runny nose.[7] After prolonged treatment, Januvia has been found to trigger pancreatitis, pancreatic and thyroid cancer.[6] However, human origin cells did not show any indication of becoming cancerous.

References

  1. ↑ Ghosh, S. & Goodsell, D. Dipeptidyl Peptidase 4: Protein Data Bank (PDB). (2016) doi:10.2210/rcsb_pdb/mom_2016_10
  2. ↑ 2.0 2.1 2.2 2.3 Gallwitz B. Review of sitagliptin phosphate: a novel treatment for type 2 diabetes. Vasc Health Risk Manag. 2007;3(2):203-10. PMID:17580730
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 Annex I: Summary of Product Characteristics, Januvia [Online] p 1-78. Merck Sharp & Dohme Ltd. http://ec.europa.eu/health/documents/community-register/2016/20160624135348/anx_135348_en.pdf (accessed Nov 12, 2016).
  4. ↑ Kim D, Wang L, Beconi M, Eiermann GJ, Fisher MH, He H, Hickey GJ, Kowalchick JE, Leiting B, Lyons K, Marsilio F, McCann ME, Patel RA, Petrov A, Scapin G, Patel SB, Roy RS, Wu JK, Wyvratt MJ, Zhang BB, Zhu L, Thornberry NA, Weber AE. (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin -7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine: a potent, orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. J Med Chem. 2005 Jan 13;48(1):141-51. PMID:15634008 doi:10.1021/jm0493156
  5. ↑ 5.0 5.1 Barnett A. DPP-4 inhibitors and their potential role in the management of type 2 diabetes. Int J Clin Pract. 2006 Nov;60(11):1454-70. PMID:17073841 doi:10.1111/j.1742-1241.2006.01178.x
  6. ↑ 6.0 6.1 6.2 Sarkar, M., et al. Double Edge Effect of DPP4 Inhibitor Sitagliptin, A Type-2 Anti-Diabetic Drug, on Inflammation, Injury and Cancer. (2016) J Stem Cell Regen Biol 2(3): 1- 7. doi:10.15436/2471-0598.16.017
  7. ↑ 7.0 7.1 Januvia (sitagliptin phosphate) Medication Guide [Online] 2013, p 1-4. U.S. Food and Drug Administration. http://www.fda.gov/downloads/drugs/drugsafety/ucm204269.pdf (accessed Nov 12, 2016).

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Andrew Nguyen

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