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@KnudsenLau_2019_DiscoveryDevelopmentLiraglutide

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Reference

Knudsen, L. B., & Lau, J. (2019). The Discovery and Development of Liraglutide and Semaglutide. Frontiers in Endocrinology, 10. https://doi.org/10.3389/fendo.2019.00155

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Reversible binding to albumin was used for the systemic protraction of liraglutide and semaglutide, with optimal fatty acid and linker combinations identified to maximize albumin binding while maintaining GLP-1 receptor (GLP-1R) potency.

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GLP-1RAs mediate their effects via this receptor, which is expressed in the pancreas, gastrointestinal tract, heart, lungs, kidneys, and brain. GLP-1Rs in the pancreas and brain have been shown to account for the respective improvements in glycemic control and body weight that are evident with liraglutide and semaglutide. Both liraglutide and semaglutide also positively affect cardiovascular (CV) outcomes in individuals with T2D

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its use in an oral formulation for the treatment of T2D

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fatty-acid derivatization

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fatty-acid derivatization was employed. The aim was to prepare analogs that could bind to albumin in a reversible manner and, thereby, protect the peptide from both DPP-IV degradation and renal filtration.

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However, while introducing Gly at position 8 reduced the DPP-IV lability of GLP-1, its affinity for the GLP-1 receptor (GLP-1R) was also significantly reduced.

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the C-terminal of GLP-1 binds to the extracellular domain, whereas the N-terminal binds to the transmembrane domain of the receptor.

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A gamma glutamate (γGlu) linker was introduced to compensate for the loss of the acidic group used for amide linkage. An initial conclusion was that fatty acids equal to, or longer than, 12 carbons atoms resulted in half-lives of more than 9 h following subcutaneous dosing compared with 1.5 h for native GLP-1.

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positions 7, 10, 12, 13, and 15 in the N-terminal, as well as positions 28 and 29 in the C-terminal, of GLP-1 were unsuitable for substitution with a fatty-acid derivatized lysine.

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there is already a lysine in position 26 available for chemical derivatization, this was a preferred position for the attachment of a fatty acid. An additional benefit was that the only other lysine, at position 34, could be substituted with arginine resulting in a GLP-1 analog that could be used in a semirecombinant process, where the peptide backbone was produced recombinantly and the fatty acid attached afterwards by a simple chemical reaction

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fatty di-acids longer than 14 carbons attached via γGlu resulted in loss of activity, while the use of mono-acids of up to 16 carbons (palmitate) retained activity

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It was concluded that the use of palmitate with a γGlu linker was the optimal combination to obtain an appropriate in vivo protraction without compromising receptor potency.

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A key property of liraglutide is its partial protection from rapid DPP-IV degradation, despite the His-Ala N-terminal being unchanged (44). This protection may be due to the reversible binding to albumin, or direct steric hindrance

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Successful clinical trials with exenatide and liraglutide led to an increased interest in GLP-1-based therapies. As daily injections are a barrier for some patients with T2D, there was focus on improving convenience, ideally with an effective GLP-1 analog that could be administered once weekly.

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Sustained release was one of the first approaches to be assessed in clinical trials, and led to approval of the encapsulated formulation of exenatide: exenatide extended release (ER)

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The Aib8 protected taspoglutide from DPP-IV degradation (48).

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The main challenge identified in earlier studies was that strong binding to albumin had a negative impact on the potency of compounds for the GLP-1R, due to competition between binding to albumin and binding to the receptor (42, 46).

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the stronger the affinity to albumin the smaller the free and active circulating fraction of the GLP-1 peptide.

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Albiglutide has a tandem repeat of Gly8 GLP-1(7-36). The purpose of the tandem repeat is likely to improve affinity for the GLP-1R, by creating a longer distance between albumin and the distal GLP-1 peptide (55). An amino acid substitution (Ala8 to Gly8) protects albiglutide from DPP-IV degradation at the N-terminal. Finally, the tandem repeat is fused to the N-terminal of HSA to extend the half-life of albiglutide. However, while the half-life was extended to 6–8 days, making it suitable for OW dosing (56), the potency of albiglutide was significantly reduced (GLP-1R affinity of albiglutide is 20 nM compared with 0.02 nM for exenatide) (55), most likely due to a combination of the Gly8 modification and the covalent attachment to HSA.

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he strategy was to keep the peptide as similar to liraglutide and endogenous GLP-1 as possible, to avoid unnecessary risks in terms of immunogenicity.

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the peptide backbone was modified at position 8 only, where Ala was substituted with Aib, previously shown to be resistant to DPP-IV cleavage and have high GLP-1R affinity (36)

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The second part of the strategy was to find the optimal combination of a fatty acid with high albumin affinity, attached to GLP-1 via a water compatible chemical linker, to ensure that the derivatized peptide had high GLP-1R potency in the presence of albumin.

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the introduction of “OEG” linkers resulted in both high receptor potency and albumin affinity. To increase albumin affinity, beyond that obtained with palmitate, the length and type of fatty acid was explored. Increasing the length of fatty acids from C16 (palmitate) to C18 or C20 did not result in the desired properties. Fatty di-acids that had a proximal fatty acid for amide connectivity to the linker, as well as a distal fatty acid, were shown to be the solution to obtaining high albumin binding and GLP-1R potency.

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Liraglutide and semaglutide are both long-acting GLP-1RAs that, despite differing administration intervals and doses, have pharmacodynamic (PD) effects for 24 h/day (124, 125). Liraglutide was developed for OD administration, and is available as a OD injection of up to 1.8 mg (126), whereas semaglutide is available as a OW injection of up to 1.0 mg (127)—both for the treatment of T2D.

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Liraglutide, which comprises natural amino acids and a C16 mono-acid, is fully metabolized in the same way as other peptides and fatty acids (44). Semaglutide, which contains an amino acid described in nature but not in humans (Aib) and a more synthetic component in the spacer region, is still fully metabolized (125)

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While GI side effects have been suggested to be involved in mediating the weight-loss effect of GLP-1RAs, analysis of large clinical trial data sets with liraglutide and semaglutide has shown that, while GI side effects may lead to more initial weight loss, they are not the mechanism of weight loss as many patients have weight loss and no side effects

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THE TECHNOLOGY BEHIND ORAL SEMAGLUTIDE, AND THE MECHANISM OF ITS ABSORPTION

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Oral delivery is known as a desirable approach in terms of patient convenience, but it has not been possible to achieve acceptable bioavailability of large hydrophilic peptides and proteins via this approach; oral absorption typically requires a low molecular weight and a certain hydrophobicity

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