Glucagon analogues

Amylin analogue Pramlintide Suppress glucagon secretion and slow gastric emptying SC injection6... 

In 1979, Ross et al 22i" measured the ODMR of tyrosine in glucagon and the derivative [12-homoarginine]glucagon to examine the effect of chemical modification of a lysine residue adjacent to Tyr-10 and Tyr-13. The guanidinated analogue had lower potency than glucagon in a fat cell hormone receptor assay. Since the tyrosine ODMR and other spectral properties of the polypeptide, including circular dichroism, were essentially identical, it was... 

Improved stability with simultaneous preservation of activity has been demonstrated with analogues of glucagon-like peptide-1 and gastric inhibitory polypeptide, two hormones that stimulate the release of insulin. Glucagon-like peptide-1 (GLP-1) is a 30-residue gastrointestinal hormone, ami-dated at the C-terminus that has potential as a treatment for type-2 diabetes. However, GLP-1 is rapidly degraded by dipeptidyl-peptidase IV (EC... 

Octreotide acetate (Sandostatin) is a synthetic peptide analogue of the hormone somatostatin. Its actions include inhibition of the pituitary secretion of growth hormone and an inhibition of pancreatic islet cell secretion of insulin and glucagon. Unlike somatostatin, which has a plasma half-life of a few minutes, octreotide has a plasma elimination half-Hfe of 1 to 2 hours. Excretion of the drug is primarily renal. 

Pramlintide (rINN) is an amyloid analogue (1). It is administered subcutaneously, but it precipitates above pH 5.5 and therefore cannot be co-administered with insulin. It received FDA approval in 2005 for both type 1 and type 2 diabetes. It reduces postprandial glucose excursions, probably by reducing stomach emptying, not by stimulating the release of glucagon-like peptide (GLP-1) (2). It can only be given by injection. 

The first and the second approaches have provided some positive results but, unfortunately, they depend upon the structure of the protein. Typical examples of sequence modifications to improve stability and pharmacokinetics are the preparation of humanized antibodies, where part of the mouse sequence is substituted by the human form, and the granulocyte colony-stimulating factor muteins, where up to seven amino acids are substituted. Examples of truncated sequence proteins with improved characteristic are the 7-36 analogues of glucagon-like peptides or the 1-29 sequence growth hormone-releasing factor [1, 2]. 

Fig. 10. Effects of glucagon, cAMP analogue and forskolin, in the presence or absence of phorbol ester, on [3H]IP3 levels in isolated rat hepatocytes. Hepatocytes were incubated for 90 min with [3H]myo-in-ositol to label the inositol phospholipids and then for 2 min with the designated compounds at the concentrations shown in the presence or absence of 1 fiM 4/8-phorbol 12/3-myristate 13a-acetate (PMA). pH]IP, was measured as described in Ref. 139. 8CPTcAMP is 8-p-chlorophenylthioadenosine 3, 5 -cyclic monophosphate. Reproduced from Ref. 5 by permission of the authors and publisher.

Glucagon causes a 30-40% inhibition of ATP-dependent Ca2+ transport activity and (Ca2+-Mg2+)-ATPase activity in liver plasma membranes [150-152]. however, much higher glucagon concentrations (0.1-10/i.M) are required to produce these changes [150-152] than to activate adenylate cyclase (0.1-100 nM), and the inhibition of the ATPase is not mimicked by cAMP or its analogues [157]. The effects of several glucagon derivatives on the ATPase are also very different from their effects on adenylate cyclase [150]. All of these observations indicate that the two effects are not related. 

Xiao Q, Giguere J, Parisien M et al. (2001) Biological activities of glucagon-like peptide-1 analogues in vitro and in vivo. Biochemistry 40 2860-2869... 

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