Abstract
Type 2 diabetes mellitus is a chronic metabolic disease that is characterized by hyperglycemia, which results from the body’s ineffective use of insulin (a gradual decline in insulin sensitivity and/or insulin secretion). It has been reported that between 347 and 371 million people worldwide currently have diabetes and that approximately 90 % have type 2 diabetes mellitus. It is forecasted that the number of diabetes deaths will double between 2005 and 2030, which will make diabetes the seventh leading cause of death in 2030.
In the USA, there are now ten different drug classes available to manage hyperglycemia in type 2 diabetic patients. However, not all of the drugs show the same level of safety (particularly cardiovascular safety). One of the most recent treatments for type 2 diabetes mellitus is the use of dipeptidyl peptidase-IV (DPP-IV) inhibitors. In addition to regulating postprandial glycemia, these drugs improve several cardiovascular risk factors. Thus, DPP-IV is a very interesting target for finding natural compounds that inhibit it and that can be used as bioactive compounds in functional food that prevents the development of type 2 diabetes mellitus.
This chapter (a) focuses on the importance of DPP-IV inhibition for type 2 diabetes prevention and treatment, (b) summarizes which natural products are known to inhibit DPP-IV, and (c) suggests how to use drug-discovery tools to improve the search for new DPP-IV inhibitors of natural origin.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
International Diabetes Federation (2013) IDF Diabetes Atlas, 6th edn. Brussels, Belgium: International Diabetes Federation, http://www.idf.org/diabetesatlas
Daousi C, Casson IF, Gill GV, MacFarlane IA, Wilding JPH, Pinkney JH (2006) Prevalence of obesity in type 2 diabetes in secondary care: association with cardiovascular risk factors. Postgrad Med J 82:280–284
UK Prospective Diabetes Study (UKPDS) Group (1998) Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 352:837–853
Kahn SE, Haffner SM, Heise MA et al (2006) Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med 355:2427–2443
Ross SA, Dzida G, Vora J, Khunti K, Kaiser M, Ligthelm RJ (2011) Impact of weight gain on outcomes in type 2 diabetes. Curr Med Res Opin 27:1431–1438
Jacobson AM (2004) Impact of improved glycemic control on quality of life in patients with diabetes. Endocr Pract 10:502–508
International Diabetes Federation. IDF diabetes atlas. http://www.idf.org/diabetesatlas. Accessed 15 Aug 2013
World Health Organization. Diabetes programme. http://www.who.int/diabetes/en/. Accessed 15 Aug 2013
Morrish NJ, Wang SL, Stevens LK, Fuller JH, Keen H (2001) Mortality and causes of death in the WHO multinational study of vascular disease in diabetes. Diabetologia 44(Suppl 2):S14–S21
World Health Organization (2011). Global status report on noncommunicable diseases 2010. http://www.who.int/nmh/publications/ncd_report2010/en/. Accessed 15 Aug 2013
Roglic G, Unwin N, Bennett PH, Mathers C, Tuomilehto J, Nag S, Connolly V, King H (2005) The burden of mortality attributable to diabetes: realistic estimates for the year 2000. Diabetes Care 28:2130–2135
World Health Organization (2011). Prevention of blindness and visual impairment. Action plan for the prevention of avoidable blindness. Global data on visual impairment 2010. http://www.who.int/entity/blindness/GLOBALDATAFINALforweb.pdf. Accessed 15 Aug 2013
Guthrie RM (2012) Evolving therapeutic options for type 2 diabetes mellitus: an overview. Postgrad Med 124:82–89
US Food and Drug Administration (2008). Guidance for industry. Diabetes mellitus—evaluating cardiovascular risk in new anti-diabetic therapies to treat type 2 diabetes. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid-ances/ucm071627.pdf. Accessed 15 Aug 2013
Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R, Zinman B (2009) Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 32:193–203
Hopsu-Havu VK, Sarimo SR (1967) Purification and characterization of an aminopeptidase hydrolyzing glycyl-proline-naphthylamide. Hoppe Seylers Z Physiol Chem 348:1540–1550
Rawlings ND, Tolle DP, Barrett AJ (2004) MEROPS: the peptidase database. Nucleic Acids Res 32:D160–D164
Power O, Nongonierma AB, Jakeman P, Fitzgerald RJ (2013) Food protein hydrolysates as a source of dipeptidyl peptidase IV inhibitory peptides for the management of type 2 diabetes. Proc Nutr Soc 73:34–46
Mendieta L, Tarrago T, Giralt E (2011) Recent patents of dipeptidyl peptidase IV inhibitors. Expert Opin Ther Pat 21:1693–1741
Gorrell MD (2005) Dipeptidyl peptidase IV and related enzymes in cell biology and liver disorders. Clin Sci (Lond) 108:277–292
Juillerat-Jeanneret L (2014) Dipeptidyl peptidase IV and its inhibitors: therapeutics for type 2 diabetes and what else? J Med Chem 57:2197–2212
Mentlein R (1999) Dipeptidyl-peptidase IV (CD26)–role in the inactivation of regulatory peptides. Regul Pept 85:9–24
Nabeno M, Akahoshi F, Kishida H, Miyaguchi I, Tanaka Y, Ishii S, Kadowaki T (2013) A comparative study of the binding modes of recently launched dipeptidyl peptidase IV inhibitors in the active site. Biochem Biophys Res Commun 434:191–196
Thoma R, Löffler B, Stihle M, Huber W, Ruf A, Hennig M (2003) Structural basis of proline-specific exopeptidase activity as observed in human dipeptidyl peptidase-IV. Structure 11:947–959
Doherty AM, Bock MG, Desai MC, Overington J, Plattner JJ, Stamford A, Wustrow D, Young H, Gwaltney SL, Stafford JA (2005) Inhibitors of dipeptidyl peptidase 4. Annu Rep Med Chem 40:149–165
Chien C-H, Huang L-H, Chou C-Y, Chen Y-S, Han Y-S, Chang G-G, Liang P-H, Chen X (2004) One site mutation disrupts dimer formation in human DPP-IV proteins. J Biol Chem 279:52338–52345
Engel M, Hoffmann T, Wagner L, Wermann M, Heiser U, Kiefersauer R, Huber R, Bode W, Demuth H-U, Brandstetter H (2003) The crystal structure of dipeptidyl peptidase IV (CD26) reveals its functional regulation and enzymatic mechanism. Proc Natl Acad Sci U S A 100:5063–5068
Pederson RA, White HA, Schlenzig D, Pauly RP, McIntosh CH, Demuth HU (1998) Improved glucose tolerance in Zucker fatty rats by oral administration of the dipeptidyl peptidase IV inhibitor isoleucine thiazolidide. Diabetes 47:1253–1258
Pospisilik JA, Stafford SG, Demuth H-U, McIntosh CHS, Pederson RA (2002) Long-term treatment with dipeptidyl peptidase IV inhibitor improves hepatic and peripheral insulin sensitivity in the VDF Zucker rat: a euglycemic-hyperinsulinemic clamp study. Diabetes 51:2677–2683
Cheng JD, Dunbrack RL, Valianou M, Rogatko A, Alpaugh RK, Weiner LM (2002) Promotion of tumor growth by murine fibroblast activation protein, a serine protease, in an animal model. Cancer Res 62:4767–4772
Kajiyama H, Kikkawa F, Suzuki T, Shibata K, Ino K, Mizutani S (2002) Prolonged survival and decreased invasive activity attributable to dipeptidyl peptidase IV overexpression in ovarian carcinoma. Cancer Res 62:2753–2757
Ho L, Aytac U, Stephens LC et al (2001) In vitro and in vivo antitumor effect of the anti-CD26 monoclonal antibody 1F7 on human CD30+ anaplastic large cell T-cell lymphoma Karpas 299. Clin Cancer Res 7:2031–2040
Ussher JR, Sutendra G, Jaswal JS (2012) The impact of current and novel anti-diabetic therapies on cardiovascular risk. Future Cardiol 8:895–912
Zhong J, Rao X, Rajagopalan S (2013) An emerging role of dipeptidyl peptidase 4 (DPP4) beyond glucose control: potential implications in cardiovascular disease. Atherosclerosis 226:305–314
Patil HR, Al Badarin FJ, Al Shami HA, Bhatti SK, Lavie CJ, Bell DSH, O’Keefe JH (2012) Meta-analysis of effect of dipeptidyl peptidase-4 inhibitors on cardiovascular risk in type 2 diabetes mellitus. Am J Cardiol 110:826–833
Frederich R, Alexander JH, Fiedorek FT, Donovan M, Berglind N, Harris S, Chen R, Wolf R, Mahaffey KW (2010) A systematic assessment of cardiovascular outcomes in the saxagliptin drug development program for type 2 diabetes. Postgrad Med 122:16–27
Scheen AJ (2013) Cardiovascular effects of gliptins. Nat Rev Cardiol 10:73–84
Simsek S, de Galan BE (2012) Cardiovascular protective properties of incretin-based therapies in type 2 diabetes. Curr Opin Lipidol 23:540–547
Dai Y, Dai D, Mercanti F, Ding Z, Wang X, Mehta JL (2013) Dipeptidyl peptidase-4 inhibitors in cardioprotection: a promising therapeutic approach. Acta Diabetol 50:827–835
Scheen AJ (2013) Cardiovascular effects of dipeptidyl peptidase-4 inhibitors: from risk factors to clinical outcomes. Postgrad Med 125:7–20
Yousefzadeh P, Wang X (2013) The effects of dipeptidyl peptidase-4 inhibitors on cardiovascular disease risks in type 2 diabetes mellitus. J Diabetes Res 2013:459821
Balakumar P, Dhanaraj SA (2013) Cardiovascular pleiotropic actions of DPP-4 inhibitors: a step at the cutting edge in understanding their additional therapeutic potentials. Cell Signal 25:1799–1803
Wang XM, Yao T-W, Nadvi NA, Osborne B, McCaughan GW, Gorrell MD (2008) Fibroblast activation protein and chronic liver disease. Front Biosci 13:3168–3180
Kirby M, Yu DMT, O’Connor S, Gorrell MD (2010) Inhibitor selectivity in the clinical application of dipeptidyl peptidase-4 inhibition. Clin Sci (Lond) 118:31–41
Lankas GR, Leiting B, Roy RS et al (2005) Dipeptidyl peptidase IV inhibition for the treatment of type 2 diabetes: potential importance of selectivity over dipeptidyl peptidases 8 and 9. Diabetes 54:2988–2994
Deacon CF, Ahrén B (2011) Physiology of incretins in health and disease. Rev Diabet Stud 8:293–306
Tortosa F, Dotta F (2013) Incretin hormones and beta-cell mass expansion: what we know and what is missing? Arch Physiol Biochem 119:161–169
Ahrén B (2013) Incretin dysfunction in type 2 diabetes: clinical impact and future perspectives. Diabetes Metab 39:195–201
Opinto G, Natalicchio A, Marchetti P (2013) Physiology of incretins and loss of incretin effect in type 2 diabetes and obesity. Arch Physiol Biochem 119:170–178
Brunton S (2013) Integrating incretin-based therapy into type 2 diabetes management. Vital Signs 62:S1–S8
Papamargaritis D, Miras AD, le Roux CW (2013) Influence of diabetes surgery on gut hormones and incretins. Nutr Hosp 28(Suppl 2):95–103
Meier JJ, Nauck MA, Schmidt WE, Gallwitz B (2002) Gastric inhibitory polypeptide: the neglected incretin revisited. Regul Pept 107:1–13
Green BD, Flatt PR, Bailey CJ (2006) Inhibition of dipeptidylpeptidase IV activity as a therapy of type 2 diabetes. Expert Opin Emerg Drugs 11:525–539
Lindgren O, Mari A, Deacon CF, Carr RD, Winzell MS, Vikman J, Ahrén B (2009) Differential islet and incretin hormone responses in morning versus afternoon after standardized meal in healthy men. J Clin Endocrinol Metab 94:2887–2892
Ahrén B, Carr RD, Deacon CF (2010) Incretin hormone secretion over the day. Vitam Horm 84:203–220
Zettl H, Schubert-Zsilavecz M, Steinhilber D (2010) Medicinal chemistry of incretin mimetics and DPP-4 inhibitors. ChemMedChem 5:179–185
Drucker DJ, Nauck MA (2006) The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet 368:1696–1705
Holst JJ, Vilsbøll T, Deacon CF (2009) The incretin system and its role in type 2 diabetes mellitus. Mol Cell Endocrinol 297:127–136
Holst JJ, Deacon CF (2004) Glucagon-like peptide 1 and inhibitors of dipeptidyl peptidase IV in the treatment of type 2 diabetes mellitus. Curr Opin Pharmacol 4:589–596
Baggio LL, Drucker DJ (2007) Biology of incretins: GLP-1 and GIP. Gastroenterology 132:2131–2157
Drucker DJ (2003) Therapeutic potential of dipeptidyl peptidase IV inhibitors for the treatment of type 2 diabetes. Expert Opin Investig Drugs 12:87–100
Højberg PV, Vilsbøll T, Rabøl R, Knop FK, Bache M, Krarup T, Holst JJ, Madsbad S (2009) Four weeks of near-normalisation of blood glucose improves the insulin response to glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide in patients with type 2 diabetes. Diabetologia 52:199–207
Hansen KB, Vilsbøll T, Bagger JI, Holst JJ, Knop FK (2012) Impaired incretin-induced amplification of insulin secretion after glucose homeostatic dysregulation in healthy subjects. J Clin Endocrinol Metab 97:1363–1370
Demuth H-U, McIntosh CHS, Pederson RA (2005) Type 2 diabetes–therapy with dipeptidyl peptidase IV inhibitors. Biochim Biophys Acta 1751:33–44
Kim S-H, Lee S-H, Yim H-J (2013) Gemigliptin, a novel dipeptidyl peptidase 4 inhibitor: first new anti-diabetic drug in the history of Korean pharmaceutical industry. Arch Pharm Res 36:1185–1188
US National Library of Medicine. National Institutes of Health. MedlinePlus (2014). Sitagliptin. http://www.nlm.nih.gov/medlineplus/druginfo/meds/a606023.html. Accessed 21 Nov 2013
US National Library of Medicine. National Institutes of Health. MedlinePlus (2014). Saxagliptin. http://www.nlm.nih.gov/medlineplus/druginfo/meds/a610003.html. Accessed 21 Nov 2013
US National Library of Medicine. National Institutes of Health. MedlinePlus (2014). Linagliptin. http://www.nlm.nih.gov/medlineplus/druginfo/meds/a611036.html. Accessed 21 Nov 2013
Noel RA, Braun DK, Patterson RE, Bloomgren GL (2009) Increased risk of acute pancreatitis and biliary disease observed in patients with type 2 diabetes: a retrospective cohort study. Diabetes Care 32:834–838
Engel SS, Williams-Herman DE, Golm GT, Clay RJ, Machotka S V, Kaufman KD, Goldstein BJ (2010) Sitagliptin: review of preclinical and clinical data regarding incidence of pancreatitis. Int J Clin Pract 64:984–990
Williams-Herman D, Engel SS, Round E, Johnson J, Golm GT, Guo H, Musser BJ, Davies MJ, Kaufman KD, Goldstein BJ (2010) Safety and tolerability of sitagliptin in clinical studies: a pooled analysis of data from 10,246 patients with type 2 diabetes. BMC Endocr Disord 10:7
Engel SS, Round E, Golm GT, Kaufman KD, Goldstein BJ (2013) Safety and tolerability of sitagliptin in type 2 diabetes: pooled analysis of 25 clinical studies. Diabetes Ther 4:119–145
Monami M, Dicembrini I, Mannucci E (2014) Dipeptidyl peptidase-4 inhibitors and pancreatitis risk: a meta-analysis of randomized clinical trials. Diabetes Obes Metab 16:48–56
Scheen A (2013) Gliptins (dipeptidyl peptidase-4 inhibitors) and risk of acute pancreatitis. Expert Opin Drug Saf 12:545–557
Deacon CF, Holst JJ (2013) Dipeptidyl peptidase-4 inhibitors for the treatment of type 2 diabetes: comparison, efficacy and safety. Expert Opin Pharmacother 14:2047–2058
Zanchi A, Lehmann R, Philippe J (2012) Anti-diabetic drugs and kidney disease–recommendations of the Swiss Society for Endocrinology and Diabetology. Swiss Med Wkly 142:w13629
Ramirez G, Morrison AD, Bittle PA (2013) Clinical practice considerations and review of the literature for the use of DPP-4 inhibitors in patients with type 2 diabetes and chronic kidney disease. Endocr Pract 19:1025–1034
Kuhn B, Hennig M, Mattei P (2007) Molecular recognition of ligands in dipeptidyl peptidase IV. Curr Top Med Chem 7:609–619
Engel M, Hoffmann T, Manhart S, Heiser U, Chambre S, Huber R, Demuth H-U, Bode W (2006) Rigidity and flexibility of dipeptidyl peptidase IV: crystal structures of and docking experiments with DPIV. J Mol Biol 355:768–783
Li C, Shen J, Li W, Lu C (2011) Possible ligand release pathway of dipeptidyl peptidase IV investigated by molecular dynamics simulations. Proteins Struct Funct Bioinforma 79:1800–1809
Schechter I, Berger A (2012) On the size of the active site in proteases. I. Papain. 1967. Biochem Biophys Res Commun 425:497–502
Weber AE (2004) Dipeptidyl peptidase IV inhibitors for the treatment of diabetes. J Med Chem 47:4135–4141
Wallace MB, Feng J, Zhang Z, Skene RJ, Shi L, Caster CL, Kassel DB, Xu R, Gwaltney SL (2008) Structure-based design and synthesis of benzimidazole derivatives as dipeptidyl peptidase IV inhibitors. Bioorg Med Chem Lett 18:2362–2367
Patel B, Ghate M (2013) Computational studies on structurally diverse dipeptidyl peptidase IV inhibitors: an approach for new anti-diabetic drug development. Med Chem Res 22:4505–4521
Al-Masri IM, Mohammad MK, Taha MO (2008) Discovery of DPP IV inhibitors by pharmacophore modeling and QSAR analysis followed by in silico screening. ChemMedChem 3:1763–1779
Aertgeerts K, Ye S, Tennant MG, Kraus ML, Rogers J, Sang B-C, Skene RJ, Webb DR, Prasad GS (2004) Crystal structure of human dipeptidyl peptidase IV in complex with a decapeptide reveals details on substrate specificity and tetrahedral intermediate formation. Protein Sci 13:412–421
Bjelke JR, Christensen J, Branner S, Wagtmann N, Olsen C, Kanstrup AB, Rasmussen HB (2004) Tyrosine 547 constitutes an essential part of the catalytic mechanism of dipeptidyl peptidase IV. J Biol Chem 279:34691–34697
Yoshida T, Akahoshi F, Sakashita H, et al (2012) Discovery and preclinical profile of teneligliptin (3-[(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl]thiazolidine): a highly potent, selective, long-lasting and orally active dipeptidyl peptidase IV inhibitor for t. Bioorg Med Chem 20:5705–5719
Yoshida T, Akahoshi F, Sakashita H, Sonda S, Takeuchi M, Tanaka Y, Nabeno M, Kishida H, Miyaguchi I, Hayashi Y (2012) Fused bicyclic heteroarylpiperazine-substituted L-prolylthiazolidines as highly potent DPP-4 inhibitors lacking the electrophilic nitrile group. Bioorg Med Chem 20:5033–5041
Edmondson SD, Mastracchio A, Cox JM et al (2009) Aminopiperidine-fused imidazoles as dipeptidyl peptidase-IV inhibitors. Bioorg Med Chem Lett 19:4097–4101
Edmondson SD, Mastracchio A, Mathvink RJ et al (2006) (2S,3S)-3-Amino-4-(3,3-difluoropyrrolidin-1-yl)-N, N-dimethyl-4-oxo-2-(4-[1,2,4]triazolo[1,5-a]-pyridin-6-ylphenyl)butanamide: a selective alpha-amino amide dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. J Med Chem 49:3614–3627
Edmondson SD, Wei L, Xu J et al (2008) Fluoroolefins as amide bond mimics in dipeptidyl peptidase IV inhibitors. Bioorg Med Chem Lett 18:2409–2413
Biftu T, Scapin G, Singh S et al (2007) Rational design of a novel, potent, and orally bioavailable cyclohexylamine DPP-4 inhibitor by application of molecular modeling and X-ray crystallography of sitagliptin. Bioorg Med Chem Lett 17:3384–3387
Eckhardt M, Langkopf E, Mark M et al (2007) 8-(3-®-aminopiperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydropurine-2,6-dione (BI 1356), a highly potent, selective, long-acting, and orally bioavailable DPP-4 inhibitor for the treatment of type 2 diabetes. J Med Chem 50:6450–6453
Kaelin DE, Smenton AL, Eiermann GJ et al (2007) 4-arylcyclohexylalanine analogs as potent, selective, and orally active inhibitors of dipeptidyl peptidase IV. Bioorg Med Chem Lett 17:5806–5811
Nordhoff S, Cerezo-Gálvez S, Deppe H, Hill O, López-Canet M, Rummey C, Thiemann M, Matassa VG, Edwards PJ, Feurer A (2009) Discovery of beta-homophenylalanine based pyrrolidin-2-ylmethyl amides and sulfonamides as highly potent and selective inhibitors of dipeptidyl peptidase IV. Bioorg Med Chem Lett 19:4201–4203
Salam NK, Nuti R, Sherman W (2009) Novel method for generating structure-based pharmacophores using energetic analysis. J Chem Inf Model 49:2356–2368
Loving K, Salam NK, Sherman W (2009) Energetic analysis of fragment docking and application to structure-based pharmacophore hypothesis generation. J Comput Aided Mol Des 23:541–554
Guasch L, Ojeda MJ, González-Abuín N et al (2012) Identification of novel human dipeptidyl peptidase-IV inhibitors of natural origin (part I): virtual screening and activity assays. PLoS One 7:e44971
Rummey C, Metz G (2007) Homology models of dipeptidyl peptidases 8 and 9 with a focus on loop predictions near the active site. Proteins 66:160–171
Janardhan S, Reddy YP (2011) Homology modeling and molecular docking studies of human DPP8 and DPP9. Int J Pharma Res Dev 2:131–146
Pitman MR, Menz RI, Abbott CA (2006) Prediction of dipeptidyl peptidase (DP) 8 structure by homology modelling. Adv Exp Med Biol 575:33–42
Tanwar O, Deora GS, Tanwar L, Kumar G, Janardhan S, Alam MM, Shaquiquzzaman M, Akhter M (2014) Novel hydrazine derivatives as selective DPP-IV inhibitors: findings from virtual screening and validation through molecular dynamics simulations. J Mol Model 20:2118
Kang NS, Ahn JH, Kim SS, Chae CH, Yoo S-E (2007) Docking-based 3D-QSAR study for selectivity of DPP4, DPP8, and DPP9 inhibitors. Bioorg Med Chem Lett 17:3716–3721
Patel BD, Ghate MD (2014) Recent approaches to medicinal chemistry and therapeutic potential of dipeptidyl peptidase-4 (DPP-4) inhibitors. Eur J Med Chem 74:574–605
Ghate M, Jain SV (2013) Structure based lead optimization approach in discovery of selective DPP4 inhibitors. Mini Rev Med Chem 13:888–914
Fukuda-Tsuru S, Anabuki J, Abe Y, Yoshida K, Ishii S (2012) A novel, potent, and long-lasting dipeptidyl peptidase-4 inhibitor, teneligliptin, improves postprandial hyperglycemia and dyslipidemia after single and repeated administrations. Eur J Pharmacol 696:194–202
Ghate M, Jain S (2014) Fragment based HQSAR modeling and docking analysis of conformationally rigid 3-azabicyclo hexane derivatives to design selective DPP-4 inhibitors. Lett Drug Des Discov 11:184–198
American Diabetes Association (2014) Standards of medical care in diabetes–2014. Diabetes Care 37(Suppl 1):S14–S80
Rollinger JM, Stuppner H, Langer T (2008) Virtual screening for the discovery of bioactive natural products. Prog drug Res 65:211, 213–249
Schuster D, Wolber G (2010) Identification of bioactive natural products by pharmacophore-based virtual screening. Curr Pharm Des 16:1666–1681
Martinez-Mayorga K, Medina-Franco JL (2009) Chemoinformatics-applications in food chemistry. Adv Food Nutr Res 58:33–56
Ferguson LLR (2009) Nutrigenomics approaches to functional foods. J Am Diet Assoc 109:452–458
Pascual I, Lopéz A, Gómez H, Chappé M, Saroyán A, González Y, Cisneros M, Charli JL, Chávez MDLA (2007) Screening of inhibitors of porcine dipeptidyl peptidase IV activity in aqueous extracts from marine organisms. Enzyme Microb Technol 40:414–419
Al-masri IM, Mohammad MK, Tahaa MO (2009) Inhibition of dipeptidyl peptidase IV (DPP IV) is one of the mechanisms explaining the hypoglycemic effect of berberine. J Enzyme Inhib Med Chem 24:1061–1066
Hamden K, Bengara A, Amri Z, Elfeki A (2013) Experimental diabetes treated with trigonelline: effect on key enzymes related to diabetes and hypertension, β-cell and liver function. Mol Cell Biochem 381:85–94
Antonyan A, De A, Vitali L, Pettinari R, Marchetti F, Gigliobianco MR, Pettinari C, Camaioni E, Lupidi G (2014) Evaluation of (arene)Ru(II) complexes of curcumin as inhibitors of dipeptidyl peptidase IV. Biochimie 99:146–152
González-Abuín N, Martínez-Micaelo N, Blay M, Pujadas G, Garcia-Vallvé S, Pinent M, Ardévol A (2012) Grape seed-derived procyanidins decrease dipeptidyl-peptidase 4 activity and expression. J Agric Food Chem 60:9055–9061
Zhang S, Lu W, Liu X, Diao Y, Bai F, Wang L, Shan L, Huang J, Li H, Zhang W (2011) Fast and effective identification of the bioactive compounds and their targets from medicinal plants via computational chemical biology approach. MedChemComm 2:471
Guasch L, Sala E, Ojeda MJ, Valls C, Bladé C, Mulero M, Blay M, Ardévol A, Garcia-Vallvé S, Pujadas G (2012) Identification of novel human dipeptidyl peptidase-IV inhibitors of natural origin (part II): in silico prediction in anti-diabetic extracts. PLoS One 7:e44972
Fan J, Johnson MH, Lila MA, Yousef G, de Mejia EG (2013) Berry and citrus phenolic compounds inhibit dipeptidyl peptidase IV: implications in diabetes management. Evid Based Complement Alternat Med 2013:479505
Parmar HS, Jain P, Chauhan DS et al (2012) DPP-IV inhibitory potential of naringin: an in silico, in vitro and in vivo study. Diabetes Res Clin Pract 97:105–111
Geng Y, Lu Z-M, Huang W, Xu H-Y, Shi J-S, Xu Z-H (2013) Bioassay-guided isolation of DPP-4 inhibitory fractions from extracts of submerged cultured of Inonotus obliquus. Molecules 18:1150–1161
Bharti SK, Krishnan S, Kumar A, Rajak KK, Murari K, Bharti BK, Gupta AK (2012) Antihyperglycemic activity with DPP-IV inhibition of alkaloids from seed extract of Castanospermum australe: investigation by experimental validation and molecular docking. Phytomedicine 20:24–31
Bellé LP, Bitencourt PER, Abdalla FH, Bona KS de, Peres A, Maders LDK, Moretto MB (2013) Aqueous seed extract of Syzygium cumini inhibits the dipeptidyl peptidase IV and adenosine deaminase activities, but it does not change the CD26 expression in lymphocytes in vitro. J Physiol Biochem 69:119–124
Lacroix IME, Li-Chan ECY (2012) Evaluation of the potential of dietary proteins as precursors of dipeptidyl peptidase (DPP)-IV inhibitors by an in silico approach. J Funct Foods 4:403–422
Nongonierma AB, Fitzgerald RJ (2014) Susceptibility of milk protein-derived peptides to dipeptidyl peptidase IV (DPP-IV) hydrolysis. Food Chem 145:845–852
Rahfeld J, Schierhorn M, Hartrodt B, Neubert K, Heins J (1991) Are diprotin A (Ile-Pro-Ile) and diprotin B (Val-Pro-Leu) inhibitors or substrates of dipeptidyl peptidase IV? Biochim Biophys Acta 1076:314–316
Tulipano G, Sibilia V, Caroli AM, Cocchi D (2011) Whey proteins as source of dipeptidyl dipeptidase IV (dipeptidyl peptidase-4) inhibitors. Peptides 32:835–838
Nongonierma AB, FitzGerald RJ (2013) Dipeptidyl peptidase IV inhibitory and antioxidative properties of milk protein-derived dipeptides and hydrolysates. Peptides 39:157–163
Silveira ST, Martínez-Maqueda D, Recio I, Hernández-Ledesma B (2013) Dipeptidyl peptidase-IV inhibitory peptides generated by tryptic hydrolysis of a whey protein concentrate rich in β-lactoglobulin. Food Chem 141:1072–1077
Hatanaka T, Inoue Y, Arima J, Kumagai Y, Usuki H, Kawakami K, Kimura M, Mukaihara T (2012) Production of dipeptidyl peptidase IV inhibitory peptides from defatted rice bran. Food Chem 134:797–802
Huang S-L, Jao C-L, Ho K-P, Hsu K-C (2012) Dipeptidyl-peptidase IV inhibitory activity of peptides derived from tuna cooking juice hydrolysates. Peptides 35:114–121
Gallego M, Aristoy M-C, Toldrá F (2013) Dipeptidyl peptidase IV inhibitory peptides generated in Spanish dry-cured ham. Meat Sci 96:757–761
Lacroix IME, Li-Chan ECY (2012) Dipeptidyl peptidase-IV inhibitory activity of dairy protein hydrolysates. Int Dairy J 25:97–102
Velarde-Salcedo AJ, Barrera-Pacheco A, Lara-González S, Montero-Morán GM, Díaz-Gois A, González de Mejia E, Barba de la Rosa AP (2013) In vitro inhibition of dipeptidyl peptidase IV by peptides derived from the hydrolysis of amaranth (Amaranthus hypochondriacus L.) proteins. Food Chem 136:758–764
Nongonierma AB, Mooney C, Shields DC, Fitzgerald RJ (2013) Inhibition of dipeptidyl peptidase IV and xanthine oxidase by amino acids and dipeptides. Food Chem 141:644–653
Li-Chan ECY, Hunag S-L, Jao C-L, Ho K-P, Hsu K-C (2012) Peptides derived from atlantic salmon skin gelatin as dipeptidyl-peptidase IV inhibitors. J Agric Food Chem 60:973–978
Uenishi H, Kabuki T, Seto Y, Serizawa A, Nakajima H (2012) Isolation and identification of casein-derived dipeptidyl-peptidase 4 (DPP-4)-inhibitory peptide LPQNIPPL from gouda-type cheese and its effect on plasma glucose in rats. Int Dairy J 22:24–30
Uchida M, Ohshiba Y, Mogami O (2011) Novel dipeptidyl peptidase-4-inhibiting peptide derived from β-lactoglobulin. J Pharmacol Sci 117:63–66
Dziuba M, Dziuba B, Iwaniak A (2009) Milk proteins as precursors of bioactive peptides. Acta Sci Pol Technol Aliment 8(1):71–90 (http://www.food.actapol.net/volume8/issue1/abstract-7.html)
Minkiewicz P, Dziuba J, Michalska J (2011) Bovine meat proteins as potential precursors of biologically active peptides—a computational study based on the BIOPEP database. Food Sci Technol Int 17:39–45
Abe M, Akiyama T, Umezawa Y, Yamamoto K, Nagai M, Yamazaki H, Ichikawa Y-I, Muraoka Y (2005) Synthesis and biological activity of sulphostin analogues, novel dipeptidyl peptidase IV inhibitors. Bioorg Med Chem 13:785–797
Akiyama T, Abe M, Harada S et al (2001) Sulphostin, a potent inhibitor for dipeptidyl peptidase IV from Streptomyces sp. MK251–43F3. J Antibiot (Tokyo) 54:744–746
Umezawa H, Aoyagi T, Ogawa K, Naganawa H, Hamada M, Takeuchi T (1984) Diprotins A and B, inhibitors of dipeptidyl aminopeptidase IV, produced by bacteria. J Antibiot (Tokyo) 37:422–425
Trellet M, Melquiond A, Bonvin A (2013) A unified conformational selection and induced fit approach to protein-peptide docking. PLoS One 8:e58769
Albericio F, Kruger HG (2012) Therapeutic peptides. Future Med Chem 4:1527–1531
Yan TR, Ho SC, Hou CL (1992) Catalytic properties of X-prolyl dipeptidyl aminopeptidase from Lactococcus lactis subsp. cremoris nTR. Biosci Biotechnol Biochem 56:704–707
Lorey S, Stöckel-Maschek A, Faust J et al (2003) Different modes of dipeptidyl peptidase IV (CD26) inhibition by oligopeptides derived from the N-terminus of HIV-1 Tat indicate at least two inhibitor binding sites. Eur J Biochem 270:2147–2156
Valli M, dos Santos RN, Figueira LD, Nakajima CH, Castro-Gamboa I, Andricopulo AD, Bolzani VS (2013) Development of a natural products database from the biodiversity of Brazil. J Nat Prod 76:439–444
Chen CY-C (2011) TCM database@Taiwan: the world’s largest traditional Chinese medicine database for drug screening in silico. PLoS One 6:e15939
Elsevier Reaxys chemistry workflow solution. http://www.reaxys.com. Accessed 20 Jan 2014
Parasuraman S (2012) Protein data bank. J Pharmacol Pharmacother 3:351–352
Irwin JJ, Sterling T, Mysinger MM, Bolstad ES, Coleman RG (2012) ZINC: a free tool to discover chemistry for biology. J Chem Inf Model 52:1757–1768
Black OF, Kelly JW (1927) Pseudo ephedrine from Ephedra alata. Am J Pharm 99:748–751
Shabana MM, Mirhom YW, Genenah AA, Aboutabl EA, Amer HA (1990) Study into wild Egyptian plants of potential medicinal activity. Ninth communication: hypoglycaemic activity of some selected plants in normal fasting and alloxanised rats. Arch Exp Veterinarmed 44:389–394
Konno C, Mizuno T, Hikino H (1985) Isolation and hypoglycemic activity of ephedrans A, B, C, D and E, glycans of Ephedra distachya herbs. Planta Med 51:162–163
Grue-Sorensen G, Spenser ID (1989) The biosynthesis of ephedrine. Can J Chem 67:998–1009
Ito K, Haruna M, Furukawa H (1975) Studies on the erythrina alkaloids. X. Alkaloids of several Erythrina plants from Singapore (author’s transl). Yakugaku Zasshi 95:358–362
Kumar A, Lingadurai S, Shrivastava TP, Bhattacharya S, Haldar PK (2011) Hypoglycemic activity of Erythrina variegata leaf in streptozotocin-induced diabetic rats. Pharm Biol 49:577–582
Oh WK, Lee C-H, Seo JH, Chung MY, Cui L, Fomum ZT, Kang JS, Lee HS (2009) Diacylglycerol acyltransferase-inhibitory compounds from Erythrina senegalensis. Arch Pharm Res 32:43–47
Na M, Jang J, Njamen D, Mbafor JT, Fomum ZT, Kim BY, Oh WK, Ahn JS (2006) Protein tyrosine phosphatase-1B inhibitory activity of isoprenylated flavonoids isolated from Erythrina mildbraedii. J Nat Prod 69:1572–1576
Bae EY, Na M, Njamen D, Mbafor JT, Fomum ZT, Cui L, Choung DH, Kim BY, Oh WK, Ahn JS (2006) Inhibition of protein tyrosine phosphatase 1B by prenylated isoflavonoids isolated from the stem bark of Erythrina addisoniae. Planta Med 72:945–948
Benn MH, Shustov G, Shustova L, Majak W, Bai Y, Fairey NA (1996) Isolation and characterization of two guanidines from Galega orientalis Lam. Cv. Gale (fodder galega). J Agric Food Chem 44:2779–2781
Vuksan V, Sievenpiper JL (2005) Herbal remedies in the management of diabetes: lessons learned from the study of ginseng. Nutr Metab Cardiovasc Dis 15:149–160
Michel KH, Sandberg F, Haglid F, Norin T (1967) Alkaloids of Haloxylon salicornicum (Moq.-Tand.) Boiss. Acta Pharm Suec 4:97–116
Brack A (1962) Verlauf der Alkaloidbildung durch den Clavicepsstamm von Pennisetum typhoideum Rich. in saprophytischer Kultur. 54. Mitteilung über Mutterkornalkaloide. Arch Pharm (Weinheim) 295:510–515
Shukla K, Narain JP, Puri P, Gupta A, Bijlani RL, Mahapatra SC, Karmarkar MG (1991) Glycaemic response to maize, bajra and barley. Indian J Physiol Pharmacol 35:249–254
Sheludko Y, Gerasimenko I, Kolshorn H, Stöckigt J (2002) New alkaloids of the sarpagine group from Rauvolfia serpentina hairy root culture. J Nat Prod 65:1006–1010
Benzi G, Villa RF, Dossena M, Vercesi L, Gorini A, Pastoris O (1984) Cerebral and cerebellar metabolic changes induced by drugs during the recovery period after profound hypoglycemia. Farmaco Sci 39:44–56
Ronchetti F, Russo G, Bombardelli E, Bonati A (1971) A new alkaloid from Rauwolfia vomitoria. Phytochemistry 10:1385–1388
Campbell JIA, Mortensen A, Mølgaard P (2006) Tissue lipid lowering-effect of a traditional Nigerian anti-diabetic infusion of Rauwolfia vomitoria foilage and Citrus aurantium fruit. J Ethnopharmacol 104:379–386
Phan MG, Phan TS, Matsunami K, Otsuka H (2006) Chemical and biological evaluation on scopadulane-type diterpenoids from Scoparia dulcis of Vietnamese origin. Chem Pharm Bull (Tokyo) 54:546–549
Latha M, Pari L, Sitasawad S, Bhonde R (2004) Scoparia dulcis, a traditional anti-diabetic plant, protects against streptozotocin induced oxidative stress and apoptosis in vitro and in vivo. J Biochem Mol Toxicol 18:261–272
Ly TT, Hewitt J, Davey RJ, Lim EM, Davis EA, Jones TW (2011) Improving epinephrine responses in hypoglycemia unawareness with real-time continuous glucose monitoring in adolescents with type 1 diabetes. Diabetes Care 34:50–52
Andrews KM, Beebe D a, Benbow JW et al (2011) 1-((3S,4S)-4-amino-1-(4-substituted-1,3,5-triazin-2-yl) pyrrolidin-3-yl)-5,5-difluoropiperidin-2-one inhibitors of DPP-4 for the treatment of type 2 diabetes. Bioorg Med Chem Lett 21:1810–1814
Aguilar-Santamaría L, Ramírez G, Nicasio P, Alegría-Reyes C, Herrera-Arellano A (2009) Anti-diabetic activities of Tecoma stans (L.) Juss. ex Kunth. J Ethnopharmacol 124:284–288
Hammouda Y, Rashid A-K, Amer MS (1964) Hypoglycaemic properties of tecomine and tecostanine. J Pharm Pharmacol 16:833–834
Van de Venter M, Roux S, Bungu LC et al (2008) Anti-diabetic screening and scoring of 11 plants traditionally used in South Africa. J Ethnopharmacol 119:81–86
Torres JL, Bobet R (2001) New flavanol derivatives from grape (Vitis vinifera) byproducts. Antioxidant aminoethylthio–flavan-3-ol conjugates from a polymeric waste fraction used as a source of flavanols. J Agric Food Chem 49:4627–4634
Pinent M, Blay M, Bladé MC, Salvadó MJ, Arola L, Ardévol A (2004) Grape seed-derived procyanidins have an antihyperglycemic effect in streptozotocin-induced diabetic rats and insulinomimetic activity in insulin-sensitive cell lines. Endocrinology 145:4985–4990
Song E-K, Hur H, Han M-K (2003) Epigallocatechin gallate prevents autoimmune diabetes induced by multiple low doses of streptozotocin in mice. Arch Pharm Res 26:559–563
Takayama H, Okazaki T, Yamaguchi K, Aimi N, Haginiwa J et al (1988) Structure of two new diterpene alkaloids, 3-epi-ignavinol and 2,3-dehydrodelcosine. Chem Pharm Bull (Tokyo) 36(8):3210–3212
Konno C, Murayama M, Sugiyama K, Arai M, Murakami M, Takahashi M, Hikino H (1985) Isolation and hypoglycemic activity of aconitans A, B, C and D, glycans of Aconitum carmichaeli roots. Planta Med 51:160–161
Howes M, Simmonds M (2005) Plants used in the treatment of diabetes. In: Soumyanath A (ed) Traditional medicines for modern times. CRC, Boca Raton.
Zhang H, Wang X-N, Lin L-P, Ding J, Yue J-M (2007) Indole alkaloids from three species of the Ervatamia genus: E. officinalis, E. divaricata, and E. divaricata Gouyahua. J Nat Prod 70:54–59
Fujii M, Takei I, Umezawa K (2009) Anti-diabetic effect of orally administered conophylline-containing plant extract on streptozotocin-treated and Goto-Kakizaki rats. Biomed Pharmacother 63:710–716
Usubillaga A (1988) Solanudine, a steroidal alkaloid from Solanum nudum. Phytochemistry 27:3031–3032
Yoshikawa M, Nakamura S, Ozaki K, Kumahara A, Morikawa T, Matsuda H (2007) Structures of steroidal alkaloid oligoglycosides, robeneosides A and B, and antidiabetogenic constituents from the Brazilian medicinal plant Solanum lycocarpum. J Nat Prod 70:210–214
Villaseñor IM, Lamadrid MRA (2006) Comparative anti-hyperglycemic potentials of medicinal plants. J Ethnopharmacol 104:129–131
El Sayed KA, Hamann MT, Abd El-Rahman HA, Zaghloul AM (1998) New pyrrole alkaloids from Solanum sodomaeum. J Nat Prod 61:848–850
Kar DM, Maharana L, Pattnaik S, Dash GK (2006) Studies on hypoglycaemic activity of Solanum xanthocarpum Schrad. & Wendl. fruit extract in rats. J Ethnopharmacol 108:251–256
Kashiwaba N, Morooka S, Ono M, Toda J, Suzuki H et al (1997) Alkaloidal constituents of the leaves of Stephania cepharantha cultivated in Japan: structure of cephasugine, a new morphinane alkaloid. Chem Pharm Bull (Tokyo) 45(3):545–548
Mosihuzzaman M, Nahar N, Ali L, Rokeya B, Khan AK et al (1994) Hypoglycemic effects of three plants from eastern himalayan belt. Diabetes Res 26(3):127–138
Semwal DK, Rawat U, Semwal R, Singh R, Singh GJP (2010) Anti-hyperglycemic effect of 11-hydroxypalmatine, a palmatine derivative from Stephania glabra tubers. J Asian Nat Prod Res 12:99–105
Tsutsumi T, Kobayashi S, Liu YY, Kontani H (2003) Anti-hyperglycemic effect of fangchinoline Isolated from Stephania tetrandra radix in streptozotocin-diabetic mice. Biol Pharm Bull 26:313–317
Beek TAV, Verpoorte R, Svendsen AB (1984) Alkaloids of Tabernaemontana eglandulosa. Tetrahedron 40(4):737
Ma D-L, Chan DS-H, Leung C-H (2013) Drug repositioning by structure-based virtual screening. Chem Soc Rev 42:2130–2141
Meslamani J, Bhajun R, Martz F, Rognan D (2013) Computational profiling of bioactive compounds using a target-dependent composite workflow. J Chem Inf Model 53:2322–2333 doi:10.1021/ci400303n
Peng S, Lin X, Guo Z, Huang N (2012) Identifying multiple-target ligands via computational chemogenomics approaches. Curr Top Med Chem 12:1363–1375
Swamidass SJ, Lu Z, Agarwal P, Butte AJ (2014) Computational approaches to drug repurposing and pharmacolog- session introduction. Pac Symp Biocomput 19:110–113
Peters J-U (2013) Polypharmacology—foe or friend? J Med Chem 56:8955–8971
Santiago DN, Pevzner Y, Durand AA, Tran M, Scheerer RR, Daniel K, Sung S-S, Woodcock HL, Guida WC, Brooks WH (2012) Virtual target screening: validation using kinase inhibitors. J Chem Inf Model 52:2192–2203
Yue R, Shan L, Yang X, Zhang W (2012) Approaches to target profiling of natural products. Curr Med Chem 19:3841–3855
Gao Z, Li H, Zhang H, Liu X, Kang L, Luo X, Zhu W, Chen K, Wang X, Jiang H (2008) PDTD: a web-accessible protein database for drug target identification. BMC Bioinformatics 9:104
Li H, Gao Z, Kang L et al (2006) TarFisDock: a web server for identifying drug targets with docking approach. Nucleic Acids Res 34:W219–W224
Laskowski RA, Swindells MB (2011) LigPlot+: multiple ligand-protein interaction diagrams for drug discovery. J Chem Inf Model 51:2778–2786
Sayle RA, Milner-White EJ (1995) RASMOL: biomolecular graphics for all. Trends Biochem Sci 20:374
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2014 Springer International Publishing Switzerland
About this chapter
Cite this chapter
Ojeda, M., Cereto-Massagué, A., Valls, C., Pujadas, G., Pujadas, G. (2014). DPP-IV, An Important Target for Antidiabetic Functional Food Design. In: Martinez-Mayorga, K., Medina-Franco, J. (eds) Foodinformatics. Springer, Cham. https://doi.org/10.1007/978-3-319-10226-9_7
Download citation
DOI: https://doi.org/10.1007/978-3-319-10226-9_7
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-10225-2
Online ISBN: 978-3-319-10226-9
eBook Packages: Chemistry and Materials ScienceChemistry and Material Science (R0)