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

Mohammed A Ibrahim; June C Serem; Megan J Bester; Albert W Neitz; Anabella R M Gaspar

doi:10.2174/0929866526666190327121731

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

Protein Pept Lett. 2019 Jul 4;26(6):403-413. doi: 10.2174/0929866526666190327121731.

Authors

Mohammed A Ibrahim^{1

2}, June C Serem³, Megan J Bester³, Albert W Neitz¹, Anabella R M Gaspar¹

Affiliations

¹ Department of Biochemistry, Genetics and Microbiology, University of Pretoria, Pretoria 0002, South Africa.
² Department of Biochemistry, Ahmadu Bello University, Zaria, Nigeria.
³ Department of Anatomy, University of Pretoria, Pretoria 0002, South Africa.

PMID: 30919765
DOI: 10.2174/0929866526666190327121731

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; amino acid residues; diabetes mellitus; disaccharidase; peptide-based therapeutics; structure-activity relationship..

MeSH terms

Binding Sites
Computer Simulation
Enzyme Inhibitors / chemistry*
Humans
Hydrogen Bonding
Hypoglycemic Agents / chemistry*
Kinetics
Molecular Docking Simulation / methods*
Peptides / chemistry*
Protein Binding
Protein Conformation
Structure-Activity Relationship
alpha-Amylases / antagonists & inhibitors*
alpha-Glucosidases / metabolism*

Substances

Enzyme Inhibitors
Hypoglycemic Agents
Peptides
alpha-Amylases
alpha-Glucosidases