Using albumin to improve the therapeutic properties of diabetes treatments

Abstract

Achieving tight glycaemic control remains an unmet need for many patients with type 2 diabetes, despite improved treatments. To meet glycaemic targets, attempts have been made to improve existing drugs and to develop new classes of drugs. Recent advances include insulin analogues that more closely mimic physiologic insulin levels, and incretin-based therapies, which capitalize on the glucoregulatory properties of native glucagon-like peptide-1 (GLP-1). Although promising, these agents are associated with limitations, including hypoglycaemia with insulin, gastrointestinal adverse events with GLP-1 receptor agonists and frequent dosing with both classes. Albumin is an abundant natural drug carrier that has been used to improve the half-life, tolerability and efficacy of a number of bioactive agents. Here, we review the physiologic roles of albumin and how albumin technologies are being used to prolong duration of action of therapies for diabetes, including insulin and incretin-based therapies.

Cross-linked human serum albumin dimer has the potential for use as a plasma-retaining agent for the fatty acid-conjugated antidiabetic drugs

“…These drugs can reversibly bind albumin through the long-chain fatty acid (myristyl, hexadecandioyl and palmitoyl fatty acid for insulin detemir, insulin degludec and liraglutide, respectively) that attached via a spacer to an amino acid in insulin or mutated GLP-1. [2,3] In this study, the fluorescent probe displacement experiment results for HSA monomer and dimer were similar, where insulin analogues and GLP-1 receptor agonist displaced DNSS but not WF in a concentration-dependent manner (Figure 3).…”

Synthesis and evaluation of novel lipidated neuromedin U analogs with increased stability and effects on food intake

“…The increased in vitro plasma stability of the lipidated analogs (corresponding to an approximately 15-fold half-life prolongation compared with native NMU) suggests that the lipidation greatly enhances the proteolytic stability of NMU. However, it should be noted that the proteolytic stability was investigated in diluted plasma and thus might not reflect a natural setting where precipitation, excretion, and a higher concentration of peptidases also impacts the pharmacokinetic profile of peptides [34]. The main peptidase cleavage sites of native NMU were found to be located in the middle and in the C-terminus.…”

“…Collectively, the present data suggest that native NMU is rapidly inactivated in mouse plasma. Acylation of peptides with long-chain fatty acids has previously been shown to facilitate noncovalent binding to serum albumin and hence, prevent proteolytic degradation and renal excretion of other peptide drugs [33][34][35][36]. Inspired by this, a series of lipidated NMU analogs were generated by introducing Lys residues on different positions followed by acylation with a γ-Glu-spaced palmitic acid.…”

“…Studies have shown that optimization of the pharmacokinetic profile of peptide drugs to facilitate once-weekly administration provides better efficacy and tolerability [34,41]. Increasing the length of the fatty acid on GLP-1 analogs has been shown to increase the plasma half-life, as the length of the fatty acid is closely related to the protraction in vivo, although this might come with the caveat of decreased receptor potency [35,37].…”

“…It has recently been shown that liraglutide gains access to the central hypothalamic regions [43]. In contrast the HSA-GLP-1 conjugate, CJC-1134, has a less pronounced effect on body weight and does not appear to cross the blood-brain barrier [34,44]. Hence, it is reasonable to assume that lipidated NMU analogs could gain access to the centrally expressed NMUR2.…”