Conjugation of ATIII‐Binding Pentasaccharides to Extend the Half‐Life of Proteins: Long‐Acting Insulin

Kort, Martin de; Gianotten, Bas; Wisse, Jeffry A. J.; Bos, Ebo; Eppink, M.H.M.; Mattaar, Ellen; Vogel, G; Dokter, Wim H.A.; Honing, Maarten; Vonsovic, Stanislava; Smit, Martin-Jan; Wijkmans, J. C. H. M.; Boeckel, C. A. A. Van

doi:10.1002/cmdc.200800053

Cited by 17 publications

(30 citation statements)

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“…[2] In this regard, several strategies are currently employed, or being investigated, to extend the pharmacokinetic and subsequentp harmacodynamic profiles of GLP-1based peptides. [8,9] The aim of the present study was to exploit more recent CarboCarrier technology [10,11] to develop effective GLP-1based molecules with sustained in vitro and in vivo antidiabet-ic activity.W eb uild upon previous knowledge that binding of GLP-1 to long-lived plasma proteins extends half-life and enables tight control over targeted drugl evels. [7] Consequently,anumber of stable GLP-1 mimetics and analogues have been successfully launchedi nto the diabetesc linic.…”

Section: Introductionmentioning

confidence: 99%

“…[8,9] The aim of the present study was to exploit more recent CarboCarrier technology [10,11] to develop effective GLP-1based molecules with sustained in vitro and in vivo antidiabet-ic activity.W eb uild upon previous knowledge that binding of GLP-1 to long-lived plasma proteins extends half-life and enables tight control over targeted drugl evels. [10] Further studies have shown that the affinity for ATIII and hence the half-life of the pentasaccharide can be modified by the degree of sulfation,w hich led to idraparinux, with ah alf-life of 11 hi nr odents, translating to 120 hi n humans. [9] Ourstrategy exploits conjugation of GLP-1 to as ynthetic pentasaccharide derived from heparin [12] that reversibly binds with high affinity to antithrombin III (ATIII).…”

Section: Introductionmentioning

confidence: 99%

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Synthesis and Evaluation of a Series of Long‐Acting Glucagon‐Like Peptide‐1 (GLP‐1) Pentasaccharide Conjugates for the Treatment of Type 2 Diabetes

et al. 2015

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The present study details the development of a family of novel D-Ala(8) glucagon-like peptide-1 (GLP-1) peptide conjugates by site specific conjugation to an antithrombin III (ATIII) binding carrier pentasaccharide through tetraethylene glycol linkers. All conjugates were found to possess potent insulin-releasing activity. Peptides with short linkers (<25 atoms) conjugated at Lys(34) and Lys(37) displayed strong GLP-1 receptor (GLP-1-R) binding affinity. All D-Ala(8) GLP-1 conjugates exhibited prominent glucose-lowering action. Biological activity of the Lys(37) short-linker peptide was evident up to 72 h post-injection. In agreement, the pharmacokinetic profile of this conjugate (t1/2 , 11 h) was superior to that of the GLP-1-R agonist, exenatide. Once-daily injection of the Lys(37) short-linker peptide in ob/ob mice for 21 days significantly decreased food intake and improved HbA1c and glucose tolerance. Islet size was decreased, with no discernible change in islet number. The beneficial effects of the Lys(37) short-linker peptide were similar to or better than either exenatide or liraglutide, another GLP-1-R agonist. In conclusion, GLP-1 peptides conjugated to an ATIII binding carrier pentasaccharide have a substantially prolonged bioactive profile compatible for possible once-weekly treatment of type 2 diabetes in humans.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Synthesis and Evaluation of a Series of Long‐Acting Glucagon‐Like Peptide‐1 (GLP‐1) Pentasaccharide Conjugates for the Treatment of Type 2 Diabetes

et al. 2015

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“…Due to its strong and specific interaction with antithrombin III in blood the pentasaccharide becomes a carrier of insulin, thereby prolonging the residence time of the small protein enormously. [15] In addition, one can think of designing various novel conjugates between well-defined oligosaccharides, proteins, antibodies, and nucleotides to enter a totally new space of molecular properties and result in improved pharmacokinetics, unprecedented mixed pharmacological profiles, new targeting opportunities, or leading to novel immunomodulating agents and synthetic vaccines.…”

Section: Chemical Biology To Provide Valuable Instruments In the Toolmentioning

confidence: 99%

The State of the Art of Chemical Biology

Kh¹,

Büchner²,

Kessler³

et al. 2008

ChemBioChem

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“…As a result, idraparinux exhibits a significantly longer half-life in humans of about 120 h compared to that of fondaparinux, which is 17 h (27,36,54). Therefore, this novel approach takes advantage of the long plasma half-life of such a high-affinity pentasaccharide to enhance the PK-PD properties of therapeutic peptides and proteins, as was previously described for ␣-NAPAP, a peptidomimetic anticoagulant drug (10), and insulin (14). The purpose of this study was to investigate whether this approach could be applied to the peptide enfuvirtide.…”

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confidence: 98%

“…While the present work was in progress, a report on the proof of principle of this technology applied to insulin appeared in the literature (14). N]asparagine-labeled residue (highlighted in boldface) were prepared by 9-fluorenylmethoxycarbonyl (Fmoc)/tert-butyl (tBu) solid-phase chemistry and were subsequently purified by reversed-phase high-pressure liquid chromatography (HPLC) by the Almac Group Ltd., United Kingdom.…”

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Long-Lasting Enfuvirtide Carrier Pentasaccharide Conjugates with Potent Anti-Human Immunodeficiency Virus Type 1 Activity

Huet¹,

Kerbarh²,

Schols

et al. 2010

Antimicrob Agents Chemother

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Enfuvirtide (also known as Fuzeon, T-20, or DP-178) is an antiretroviral fusion inhibitor which prevents human immunodeficiency virus type 1 (HIV-1) from entering host cells. This linear 36-mer synthetic peptide is indicated, in combination with other antiretroviral agents, for the treatment of HIV-1-infected individuals and AIDS patients with multidrug-resistant HIV infections. Although enfuvirtide is an efficient anti-HIV-1 drug, its clinical use is limited by a short plasma half-life, i.e., approximately 2 h, which requires twice-daily subcutaneous injections, often resulting in skin sensitivity reaction side effects at the injection sites. Ultimately, 80% of patients stop enfuvirtide treatment within 6 months because of these side effects. We report on the development of long-lasting enfuvirtide conjugates by the use of the site-specific conjugation of enfuvirtide to an antithrombin-binding carrier pentasaccharide (CP) through polyethylene glycol (PEG) linkers of various lengths. These conjugates showed consistent and broad anti-HIV-1 activity in the nanomolar range. The coupling of the CP to enfuvirtide only moderately affected the in vitro anti-HIV-1 activity in the presence of antithrombin. Most importantly, one of these conjugates, enfuvirtide-PEG 12 -CP (EP40111), exhibited a prolonged elimination half-life of more than 10 h in rat plasma compared to the half-life of native enfuvirtide, which was 2.8 h. On the basis of the pharmacokinetic properties of antithrombin-binding pentasaccharides, the anticipated half-life of EP40111 in humans would putatively be about 120 h, which would allow subcutaneous injection once a week instead of twice daily. In conclusion, EP40111 is a promising compound with strong potency as a novel long-lasting anti-HIV-1 drug.Enfuvirtide (also known as Fuzeon, T-20, or DP-178) is a well-described antiviral fusion inhibitor which prevents human immunodeficiency virus type 1 (HIV-1) from entering host cells (28,38,57). This linear 36-mer synthetic peptide is indicated, in combination with other antiretroviral agents, for the treatment of HIV-1-infected individuals and AIDS patients with multidrug-resistant HIV infections who no longer respond to current highly active antiretroviral therapies (i.e., HIV reverse transcriptase and protease inhibitors). Because enfuvirtide interferes with an earlier stage of infection than highly active antiretroviral therapies, no development of cross-resistance to existing antiretroviral drugs is expected, given their distinct mechanisms of action (9,31,32,35,43). Recently, the small molecule maraviroc (Selzentry/Celsentry; Pfizer), which acts as a chemokine receptor 5 (CCR5) antagonist, was the second HIV entry inhibitor to receive approval from the U.S. FDA (16,19).The entry of HIV-1 into target cells is mediated by the viral envelope, which is a trimer consisting of three surface gp120 glycoproteins noncovalently associated with three transmembrane gp41 subunits (17,20,26). The extracellular domain (ectodomain) of gp41 is the key structure respon...

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Conjugation of ATIII‐Binding Pentasaccharides to Extend the Half‐Life of Proteins: Long‐Acting Insulin

Cited by 17 publications

References 45 publications

Synthesis and Evaluation of a Series of Long‐Acting Glucagon‐Like Peptide‐1 (GLP‐1) Pentasaccharide Conjugates for the Treatment of Type 2 Diabetes

Synthesis and Evaluation of a Series of Long‐Acting Glucagon‐Like Peptide‐1 (GLP‐1) Pentasaccharide Conjugates for the Treatment of Type 2 Diabetes

The State of the Art of Chemical Biology

Long-Lasting Enfuvirtide Carrier Pentasaccharide Conjugates with Potent Anti-Human Immunodeficiency Virus Type 1 Activity

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