TY - JOUR
T1 - Peptide degradation and the role of DPP-4 inhibitors in the treatment of type 2 diabetes
AU - Deacon, Carolyn F
N1 - Copyright © 2017 Elsevier Inc. All rights reserved.
PY - 2018/2
Y1 - 2018/2
N2 - Dipeptidyl peptidase-4 (DPP-4) inhibitors are now a widely used, safe and efficacious class of antidiabetic drugs, which were developed prospectively using a rational drug design approach based on a thorough understanding of the endocrinology and degradation of glucagon-like peptide-1 (GLP-1). GLP-1 is an intestinal hormone with potent insulinotropic and glucagonostatic effects and can normalise blood glucose levels in patients with type 2 diabetes, but the native peptide is not therapeutically useful because of its inherent metabolic instability. Using the GLP-1/DPP-4 system and type 2 diabetes as an example, this review summarises how knowledge of a peptide's biological effects coupled with an understanding of the pathways involved in its metabolic clearance can be exploited in a rational, step-by-step manner to develop a therapeutic agent, which is effective and well tolerated, and any side effects are minor and largely predictable. Other peptides with metabolic effects which can also be degraded by DPP-4 will be reviewed, and their potential role as additional mediators of the effects of DPP-4 inhibitors will be assessed.
AB - Dipeptidyl peptidase-4 (DPP-4) inhibitors are now a widely used, safe and efficacious class of antidiabetic drugs, which were developed prospectively using a rational drug design approach based on a thorough understanding of the endocrinology and degradation of glucagon-like peptide-1 (GLP-1). GLP-1 is an intestinal hormone with potent insulinotropic and glucagonostatic effects and can normalise blood glucose levels in patients with type 2 diabetes, but the native peptide is not therapeutically useful because of its inherent metabolic instability. Using the GLP-1/DPP-4 system and type 2 diabetes as an example, this review summarises how knowledge of a peptide's biological effects coupled with an understanding of the pathways involved in its metabolic clearance can be exploited in a rational, step-by-step manner to develop a therapeutic agent, which is effective and well tolerated, and any side effects are minor and largely predictable. Other peptides with metabolic effects which can also be degraded by DPP-4 will be reviewed, and their potential role as additional mediators of the effects of DPP-4 inhibitors will be assessed.
KW - Dipeptidyl peptidase.4
KW - Glucagon-like peptide-1
KW - Incretin
KW - Peptide degradation
KW - Therapy
KW - Type 2 diabetes
UR - http://www.scopus.com/inward/record.url?scp=85041483511&partnerID=8YFLogxK
U2 - 10.1016/j.peptides.2017.10.011
DO - 10.1016/j.peptides.2017.10.011
M3 - Journal article
C2 - 29412814
SN - 0196-9781
VL - 100
SP - 150
EP - 157
JO - Peptides
JF - Peptides
ER -
