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Protein & Peptide Letters

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ISSN (Print): 0929-8665
ISSN (Online): 1875-5305

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Research Article

Structure - Function Analysis of Peptide Analogs of SQSPA with Respect to α-glucosidase and α-amylase Inhibition

Author(s): Mohammed A. Ibrahim*, June C. Serem, Megan J. Bester, Albert W. Neitz and Anabella R.M. Gaspar

Volume 26, Issue 6, 2019

Page: [403 - 413] Pages: 11

DOI: 10.2174/0929866526666190327121731

Price: $65

Abstract

Background: Peptide-based therapeutics offer a unique avenue for the development of novel agents for the treatment of diabetes mellitus including α-glucosidase inhibitors. The peptide, SQSPA, was reported to possess to α -glucosidase inhibitory activity in addition to resistance to Gastrointestinal Tract (GIT) digestion.

Methods: In this study, the in silico and in vitro structure-activity analyses of the peptide was conducted using alanine scanning to identify key amino acid residues.

Results: The alanine scanning led to four analogs viz; AQSPA, SASPA, SQAPA and SQSAA which were GIT stable. Initially, the peptides were subjected to molecular docking on human α- glucosidase and α -amylase where the binding affinities to the enzymes were in the order; AQSPA>SASPA>SQSPA>SQAPA> SQSAA and AQSPA>SQSAA>SASPA>SQSPA> SQAPA, respectively. Hydrogen bond were important for the binding of all peptides but SASPA and AQSPA had the highest hydrogen bonds interactions with the α-glucosidase and α-amylase, respectively. In vitro analysis revealed that the α -glucosidase and α-amylase inhibitory activities of the peptides were in the order AQSPA>SQSPA>SQAPA>SASPA>SQSAA and AQSPA>SASPA> SQAPA>SQSPA>SQSAA, respectively. Using inhibition kinetics, SQSPA was a mixed inhibitor of α-glucosidase while AQSPA, SQAPA and SQSAA showed non-competitive inhibition. For α- amylase inhibition, SQSPA was a non-competitive inhibitor while AQSPA and SQSAA were mixed inhibitors; SASPA and SQAPA showed uncompetitive inhibition.

Conclusion: The results indicated that P4 and Q2 are important requirements for the α-glucosidase and α-amylase inhibitory activities of the parent peptide, SQSPA. Furthermore, alanine scanning has led to the design of a novel α-glucosidase inhibitory peptide, AQSPA, with increased activities.

Keywords: Alanine scanning, diabetes mellitus, disaccharidase, peptide-based therapeutics, structure-activity relationship, amino acid residues.

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[1]
Rastogi, S.; Shukla, S.; Kalaivani, M.; Singh, G.N. Peptide-based therapeutics: Quality specifications, regulatory considerations, and prospects. Drug Discov. Today, 2018, 18, 1359-6446.
[2]
Craik, D.J.; Fairlie, D.P.; Liras, S.; Price, D. The future of peptide‐based drugs. Chem. Biol. Drug Des., 2013, 81(1), 136-147.
[3]
Fosgerau, K.; Hoffmann, T. Peptide therapeutics: Current status and future directions. Drug Discov. Today, 2015, 20, 122-128.
[4]
Vlieghe, P.; Lisowski, V.; Martinez, J.; Khrestchatisky, M. Synthetic therapeutic peptides: Science and market. Drug Discov. Today, 2010, 15, 40-56.
[5]
Vagner, J.; Qu, H.; Hruby, V. Peptidomimetics, a synthetic tool of drug discovery. Curr. Opin. Chem. Biol., 2008, 12, 292-296.
[6]
Eustache, S.; Leprince, J.; Tufféry, P. Progress with peptide scanning to study structure-activity relationships: The implications for drug discovery. Expert Opin. Drug Disc., 2016, 11(8), 771-784.
[7]
Cho, N.H.; Shaw, J.E.; Karuranga, S.; Huang, Y.; da Rocha Fernandes, J.D.; Ohlrogge, A.W.; Malanda, B. Diabetes atlas: Global estimates of diabetes prevalence for 2017 and projections for 2045. Diabetes Res. Clin. Pract., 2018, 138, 271-281.
[8]
Zhang, L.; Chen, Q.; Li, L.; Kwong, J.S.W.; Jia, P.; Zhao, P.; Wang, W.; Zhou, X.; Zhang, M.; Sun, X. α-Glucosidase inhibitors and hepatotoxicity in type 2 diabetes: A systematic review and meta-analysis. Sci. Rep., 2016, 6, 32649.
[9]
Kerru, N.; Singh-Pillay, A.; Awolade, P.; Singh, P. Current anti-diabetic agents and their molecular targets: A review. Eur. J. Med. Chem., 2018, 152, 436-488.
[10]
Ibrahim, M.A.; Bester, M.J.; Neitz, A.W.; Gaspar, A.R.M. Structural properties of bioactive peptides with α-glucosidase inhibitory activity. Chem. Biol. Drug Des., 2018, 91(2), 370-379.
[11]
Ibrahim, M.A.; Bester, M.J.; Neitz, A.W.H.; Gaspar, A.R.M. Rational in silico design of α-glucosidase inhibitory peptides and in vitro evaluation of promising candidates. Biomed. Pharm, 2018, 107, 234-242.
[12]
Jamieson, A.G.; Boutard, N.; Sabatino, D.; Lubell, W.D. Peptide scanning for studying structure-activity relationships in drug discovery. Chem. Biol. Drug Des., 2013, 81(1), 148-165.
[13]
Cantisani, M.; Finamore, E.; Mignogna, E.; Falanga, A.; Nicoletti, G.F.; Pedone, C.; Morelli, G.; Leone, M.; Galdiero, M.; Galdiero, S. Structural insights and activity analysis of the antimicrobial peptide myxinidin. Antimicrob. Agents Chemother., 2014, 58(9), 5280-5290.
[14]
Xie, J.; Li, Y.; Li, J.; Yan, Z.; Wang, D.; Guo, X.; Zhang, J.; Zhang, B.; Mou, L.; Yang, W.; Jiang, X. Potent effects of amino acid scanned antimicrobial peptide Feleucin-K3 analogs against both multidrug-resistant strains and biofilms of Pseudomonas aeruginosa. Amino Acids, 2018, 50, 1471-1483.
[15]
Savio, A.S.; Acosta, O.R.; Pérez, H.G.; Álvarez, Y.R.; Chico, A.; Pérez, H.G.; Ojeda, M.O.; Aguero, C.A.A.; Estévez, M.; Nieto, G.G. Enhancement of the inhibitory effect of an IL-15 antagonist peptide by alanine scanning. J. Pept. Sci., 2012, 18(1), 25-29.
[16]
Yang, B.; Li, X.; Zhang, C.; Yan, S.; Wei, W.; Wang, X.; Deng, X.; Qian, H.; Lin, H.; Huang, W. Design, synthesis and biological evaluation of novel peptide MC2 analogues from Momordica charantia as potential anti-diabetic agents. Org. Biomol. Chem., 2015, 13(15), 4551-4561.
[17]
Pettersen, E.F.; Goddard, T.D.; Huang, C.C.; Couch, G.S.; Greenblatt, D.M.; Meng, E.C.; Ferrin, T.E. UCSF Chimera. A visualization system for exploratory research and analysis. J. Comput. Chem., 2004, 25, 1605-1612.
[18]
Trott, O.; Olson, A.J. Auto Dock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization and multithreading. J. Comput. Chem., 2010, 31, 455-461.
[19]
Ibrahim, M.A.; Koorbanally, N.; Islam, M.S. Anti-oxidative activity and inhibition of key enzymes linked to type 2 diabetes (α-glucosidase and α-amylase) by Khaya senegalensis. Acta Pharm., 2014, 64, 311-324.
[20]
Shai, L.J.; Masoko, P.; Mokgotho, M.P.; Magano, S.P.; Mogale, A.M.; Boaduo, N.; Eloff, J.N. Yeast alpha glucosidase inhibitory and antioxidant activities of six medicinal plants collected in Phalaborwa, South Africa. S. Afr. J. Bot., 2010, 76, 465-470.
[21]
Zhang, Y.; Wang, N.; Wang, W.; Wang, J.; Zhu, Z.; Li, X. Molecular mechanisms of novel peptides from silkworm pupae that inhibit α-glucosidase. Peptides, 2016, 76, 45-50.
[22]
Proença, C.; Freitas, M.; Ribeiro, D.; Oliveira, E.F.; Sousa, J.L.; Tomé, S.M.; Ramos, M.J.; Silva, A.M.; Fernandes, P.A.; Fernandes, E. α-Glucosidase inhibition by flavonoids: An in vitro and in silico structure-activity relationship study. J. Enzy Inh. Med. Chem., 2017, 32(1), 1216-1228.
[23]
Piparo, E.L.; Scheib, H.; Frei, N.; Williamson, G.; Grigorov, M.; Chou, C.J. Flavonoids for controlling starch digestion: Structural requirements for inhibiting human α-amylase. J. Med. Chem., 2008, 51, 3555-3561.
[24]
Xu, H. Inhibition kinetics of flavonoids on yeast α-glucosidase merged with docking simulations. Protein Pept. Lett., 2010, 17, 1270-1279.
[25]
Ibrahim, M.A.; Habila, J.D.; Koorbanally, N.A.; Islam, M.S. α-Glucosidase and α-amylase inhibitory compounds from three African medicinal plants: An enzyme kinetics approach. Nat. Prod. Comm., 2017, 12(7), 1125-1128.
[26]
Kang, M.; Yi, S.; Lee, J. Production and characterization of a new α-glucosidase inhibitory peptide from Aspergillus oryzae N159-1. Mycology, 2013, 41(3), 149-154.
[27]
Yu, Z.; Yin, Y.; Zhao, W.; Yu, Y.; Liu, B.; Liu, J.; Chen, F. Novel peptides derived from egg white protein inhibiting alpha-glucosidase. Food Chem., 2011, 129(4), 1376-1382.
[28]
Zambrowicz, A.; Pokora, M.; Setner, B.; Dabrowska, A.; Szoltysik, M.; Babij, K.; Szewczuk, Z.; Trziszka, T.; Lubec, G. Multifunctional peptides derived from an egg yolk protein hydrolysate: Isolation and characterization. Amino Acids, 2015, 47, 369-380.
[29]
Meisel, H. Multifunctional peptides encrypted in milk proteins. Biofactors, 2004, 21, 55-61.
[30]
Nongonierma, A.B.; FitzGerald, R.J. Structure activity relationship modelling of milk protein-derived peptides with dipeptidyl peptidase IV (DPP-IV) inhibitory activity. Peptides, 2016, 79, 1-7.
[31]
Ling, Y.; Liping, S.; Yongliang, Z. Preparation and identification of novel inhibitory angiotensin-I-converting enzyme peptides from tilapia skin gelatin hydrolysates: Inhibition kinetics and molecular docking. Food Funct., 2018, 9, 5251.
[32]
Kuzmic, P.; Elrod, K.C.; Cregar, L.M.; Sideris, S.; Rai, R.; Janc, J.W. High- throughput screening of enzyme inhibitors: Simultaneous determination of tight- binding inhibition constants and enzyme concentration. Anal. Biochem., 2000, 286, 45-50.
[33]
Kuzmic, P. Optimal design for the dose-response screening of tight-binding enzyme inhibitors. Anal. Biochem., 2011, 419, 117-122.
[34]
Ibrahim, M.A.; Koorbanally, N.; Islam, M.S. Anti-oxidative, α-glucosidase and α- amylase inhibitory activity of Vitex doniana: Possible exploitation in the management of type 2 diabetes. Acta Pol. Pharm., 2016, 73(5), 1235-1247.

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