Sequence-based knowledge driven structural design of peptide drugs as co-agonists of GLP-1/GCG receptors.

Abstract

More than one-third of all clinically approved drugs target the G-protein coupled family of receptors (GPCRs) making them one of the most promising therapeutic targets. Bioactive peptides have emerged as an attractive alternative to conventional drug therapy. These biologically active pharmaceutical ingredients (APIs) could treat metabolic disorders such as type-2 diabetes mellitus and obesity, by targeting the two different classes of B1 G-protein coupled receptors (GCGR & GLP-1R, glucagon and glucagon-like peptide-1 receptor, respectively). However, there is a lack of experimental structural data relating to drug stability and binding to these GPCRs. In addition, a common side effect of obesity is prevalent amongst these APIs, since the incretin-mimetic drugs may stimulate insulin release by not only activating the GLP-1 receptor, but also inhibiting GCG release causing weight gain. To address the two issues in conjunction, an emerging class of dual-acting GCG/GLP-1 receptor agonists promise better control of blood sugar levels and obesity than currently marketed mono-agonist treatments. Here we present atomistic molecular dynamics-derived rules for designing bioactive peptide APIs with improved dual-acting capacities for both GLP-1 and GCG receptors. Our data identifies co-agonist peptide sequences with superior binding affinities and specificities to both these receptors and compares them against reference drug-lead and endogenous ligands for both receptors GLP-1R and GCGR.