Monoconjugation of Human Amylin with Methylpolyethyleneglycol

Sisnande, Tháyna; Guerreiro, Luiz Henrique; Braga, Raquel Rennó; Jotha-Mattos, Luana; Erthal, Luiza C. S.; Tinoco, Priscilla; Ferreira, Bruno M.; Lima, L.M.T.R.

doi:10.1371/journal.pone.0138803

Cited by 21 publications

(14 citation statements)

References 81 publications

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“…However, the pharmacology reported for these cell lines is not straight forward. Despite this, MCF‐7 cells have been used in several studies as an amylin receptor model (Sisnande et al, ; Shi et al, ). These cells are reported to express mRNA encoding two distinct splice variants of CTR, RAMP1 and RAMP3 (Chen et al, ; Ellegaard et al, ).…”

Section: The Challenges Of Pharmacology In Non‐transfected Cell Systemsmentioning

confidence: 99%

Update on the pharmacology of calcitonin/CGRP family of peptides: IUPHAR Review 25

Hay

Garelja

Poyner

et al. 2017

British J Pharmacology

295

441

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The calcitonin/CGRP family of peptides includes calcitonin, α and β CGRP, amylin, adrenomedullin (AM) and adrenomedullin 2/intermedin (AM2/IMD). Their receptors consist of one of two GPCRs, the calcitonin receptor (CTR) or the calcitonin receptor-like receptor (CLR). Further diversity arises from heterodimerization of these GPCRs with one of three receptor activity-modifying proteins (RAMPs). This gives the CGRP receptor (CLR/RAMP1), the AM and AM receptors (CLR/RAMP2 or RAMP3) and the AMY AMY and AMY receptors (CTR/RAMPs1-3 complexes, respectively). Apart from the CGRP receptor, there are only peptide antagonists widely available for these receptors, and these have limited selectivity, thus defining the function of each receptor in vivo remains challenging. Further challenges arise from the probable co-expression of CTR with the CTR/RAMP complexes and species-dependent splice variants of the CTR (CT and CT ). Furthermore, the AMY receptor is activated equally well by both amylin and CGRP, and the preferred receptor for AM2/IMD has been unclear. However, there are clear therapeutic rationales for developing agents against the various receptors for these peptides. For example, many agents targeting the CGRP system are in clinical trials, and pramlintide, an amylin analogue, is an approved therapy for insulin-requiring diabetes. This review provides an update on the pharmacology of the calcitonin family of peptides by members of the corresponding subcommittee of the International Union of Basic and Clinical Pharmacology and colleagues.

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Section: The Challenges Of Pharmacology In Non‐transfected Cell Systemsmentioning

confidence: 99%

Update on the pharmacology of calcitonin/CGRP family of peptides: IUPHAR Review 25

Hay

Garelja

Poyner

et al. 2017

British J Pharmacology

295

441

View full text Add to dashboard Cite

show abstract

“…Formulating monomeric insulin requires new excipients, which do not promote the R 6 hexamer, but still imbue insulin with sufficient stability to prevent aggregation and denaturation over time. [24,25] Covalent PEGylation has been successful as a strategy to stabilize insulin in formulation; [26][27][28] however, the extended pharmacokinetics in vivo associated with PEGylation is not desirable for rapid acting insulins. [29] Recent research has demonstrated non-covalent modification of proteins as a strategy to enhance their stability in formulation.…”

Section: Introductionmentioning

confidence: 99%

Stable Monomeric Insulin Formulations Enabled by Supramolecular PEGylation of Insulin Analogues

Maikawa

Smith

Zou

et al. 2019

Advanced Therapeutics

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Current "fast-acting" insulin analogues contain amino acid modifications meant to inhibit dimer formation and shift the equilibrium of association states toward the monomeric state. However, the insulin monomer is highly unstable and current formulation techniques require insulin to primarily exist as hexamers to prevent aggregation into inactive and immunogenic amyloids. Insulin formulation excipients have thus been traditionally selected to promote insulin association into the hexameric form to enhance formulation stability. This study exploits a novel excipient for the supramolecular PEGylation of insulin analogues, including aspart and lispro, to enhance the

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“…A new class of excipients are needed for protein formulation to address concerns surrounding aggregation and denaturation over time. [ 25 , 26 ] Covalent PEGylation has been successful as a strategy to stabilize insulin and amylin in formulation; [ 27 – 29 ] however, covalent modification of proteins often interferes with their activity, typically extends their pharmacokinetics in vivo , and can lead to increased immunogenicity. [ 30 ] Recent research has shown that non-covalent modification of proteins can enhance their stability in formulation.…”

mentioning

confidence: 99%

A co-formulation of supramolecularly stabilized insulin and pramlintide enhances mealtime glucagon suppression in diabetic pigs

et al. 2020

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In diabetic patients, treatment with insulin and pramlintide (an amylin analogue) is more effective than treatment with insulin only. But because mixtures of insulin and pramlintide are unstable and have to be injected separately, amylin analogues are only used by 1.5% of diabetics needing rapid-acting insulin. Here, we show that the supramolecular modification of insulin and pramlintide with cucurbit[7]uril-conjugated polyethylene glycol improves the pharmacokinetics of the dual-hormone therapy and enhances post-prandial glucagon suppression in diabetic pigs. The co-formulation is stable for over 100 hours at 37 ºC under continuous agitation, whereas commercial formulations of insulin analogues aggregate after 10 hours under similar conditions. In diabetic rats, the administration of the stabilized co-formulation increased the area-of-overlap ratio of the pharmacokinetic curves of pramlintide and insulin to 0.7 ± 0.1 from 0.4 ± 0.2 (mean ± s.d.) for the separate administration of the hormones. The co-administration of supramolecularly stabilized insulin and pramlintide better mimics the endogenous kinetics of co-secreted insulin and amylin, and holds promise as a dual-hormone replacement therapy.

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Monoconjugation of Human Amylin with Methylpolyethyleneglycol

Cited by 21 publications

References 81 publications

Update on the pharmacology of calcitonin/CGRP family of peptides: IUPHAR Review 25

Update on the pharmacology of calcitonin/CGRP family of peptides: IUPHAR Review 25

Stable Monomeric Insulin Formulations Enabled by Supramolecular PEGylation of Insulin Analogues

A co-formulation of supramolecularly stabilized insulin and pramlintide enhances mealtime glucagon suppression in diabetic pigs

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