Minimizing Mitogenic Potency of Insulin Analogues Through Modification of a Disulfide Bond
The mechanisms by which insulin activates the insulin receptor to promote metabolic processes and cellular growth are still not clear. Significant advances have been gained from recent structural studies in understanding how insulin binds to its receptor. However, the way in which specific interacti...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-06-01
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| Series: | Frontiers in Endocrinology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fendo.2022.907864/full |
| _version_ | 1828804680990326784 |
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| author | Shee Chee Ong Alessia Belgi Allanah L. Merriman Carlie A. Delaine Bianca van Lierop Sofianos Andrikopoulos Andrea J. Robinson Briony E. Forbes |
| author_facet | Shee Chee Ong Alessia Belgi Allanah L. Merriman Carlie A. Delaine Bianca van Lierop Sofianos Andrikopoulos Andrea J. Robinson Briony E. Forbes |
| author_sort | Shee Chee Ong |
| collection | DOAJ |
| description | The mechanisms by which insulin activates the insulin receptor to promote metabolic processes and cellular growth are still not clear. Significant advances have been gained from recent structural studies in understanding how insulin binds to its receptor. However, the way in which specific interactions lead to either metabolic or mitogenic signalling remains unknown. Currently there are only a few examples of insulin receptor agonists that have biased signalling properties. Here we use novel insulin analogues that differ only in the chemical composition at the A6–A11 bond, as it has been changed to a rigid, non-reducible C=C linkage (dicarba bond), to reveal mechanisms underlying signaling bias. We show that introduction of an A6-A11 cis-dicarba bond into either native insulin or the basal/long acting insulin glargine results in biased signalling analogues with low mitogenic potency. This can be attributed to reduced insulin receptor activation that prevents effective receptor internalization and mitogenic signalling. Insight gained into the receptor interactions affected by insertion of an A6-A11 cis-dicarba bond will ultimately assist in the development of new insulin analogues for the treatment of diabetes that confer low mitogenic activity and therefore pose minimal risk of promoting cancer with long term use. |
| first_indexed | 2024-12-12T07:44:42Z |
| format | Article |
| id | doaj.art-a3aaeb206dde409cae3f877af9454a36 |
| institution | Directory Open Access Journal |
| issn | 1664-2392 |
| language | English |
| last_indexed | 2024-12-12T07:44:42Z |
| publishDate | 2022-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Endocrinology |
| spelling | doaj.art-a3aaeb206dde409cae3f877af9454a362022-12-22T00:32:40ZengFrontiers Media S.A.Frontiers in Endocrinology1664-23922022-06-011310.3389/fendo.2022.907864907864Minimizing Mitogenic Potency of Insulin Analogues Through Modification of a Disulfide BondShee Chee Ong0Alessia Belgi1Allanah L. Merriman2Carlie A. Delaine3Bianca van Lierop4Sofianos Andrikopoulos5Andrea J. Robinson6Briony E. Forbes7Discipline of Medical Biochemistry, Flinders Health and Medical Research Institute, Flinders University of South Australia, Bedford Park, SA, AustraliaSchool of Chemistry, Monash University, Clayton, VIC, AustraliaDiscipline of Medical Biochemistry, Flinders Health and Medical Research Institute, Flinders University of South Australia, Bedford Park, SA, AustraliaDiscipline of Medical Biochemistry, Flinders Health and Medical Research Institute, Flinders University of South Australia, Bedford Park, SA, AustraliaSchool of Chemistry, Monash University, Clayton, VIC, AustraliaDepartment of Medicine, University of Melbourne, Parkville, VIC, AustraliaSchool of Chemistry, Monash University, Clayton, VIC, AustraliaDiscipline of Medical Biochemistry, Flinders Health and Medical Research Institute, Flinders University of South Australia, Bedford Park, SA, AustraliaThe mechanisms by which insulin activates the insulin receptor to promote metabolic processes and cellular growth are still not clear. Significant advances have been gained from recent structural studies in understanding how insulin binds to its receptor. However, the way in which specific interactions lead to either metabolic or mitogenic signalling remains unknown. Currently there are only a few examples of insulin receptor agonists that have biased signalling properties. Here we use novel insulin analogues that differ only in the chemical composition at the A6–A11 bond, as it has been changed to a rigid, non-reducible C=C linkage (dicarba bond), to reveal mechanisms underlying signaling bias. We show that introduction of an A6-A11 cis-dicarba bond into either native insulin or the basal/long acting insulin glargine results in biased signalling analogues with low mitogenic potency. This can be attributed to reduced insulin receptor activation that prevents effective receptor internalization and mitogenic signalling. Insight gained into the receptor interactions affected by insertion of an A6-A11 cis-dicarba bond will ultimately assist in the development of new insulin analogues for the treatment of diabetes that confer low mitogenic activity and therefore pose minimal risk of promoting cancer with long term use.https://www.frontiersin.org/articles/10.3389/fendo.2022.907864/fullinsulindicarba insulininsulin receptorbiased signalling agonistsmitogenicextracellular-signal-regulated kinase (ERK) |
| spellingShingle | Shee Chee Ong Alessia Belgi Allanah L. Merriman Carlie A. Delaine Bianca van Lierop Sofianos Andrikopoulos Andrea J. Robinson Briony E. Forbes Minimizing Mitogenic Potency of Insulin Analogues Through Modification of a Disulfide Bond Frontiers in Endocrinology insulin dicarba insulin insulin receptor biased signalling agonists mitogenic extracellular-signal-regulated kinase (ERK) |
| title | Minimizing Mitogenic Potency of Insulin Analogues Through Modification of a Disulfide Bond |
| title_full | Minimizing Mitogenic Potency of Insulin Analogues Through Modification of a Disulfide Bond |
| title_fullStr | Minimizing Mitogenic Potency of Insulin Analogues Through Modification of a Disulfide Bond |
| title_full_unstemmed | Minimizing Mitogenic Potency of Insulin Analogues Through Modification of a Disulfide Bond |
| title_short | Minimizing Mitogenic Potency of Insulin Analogues Through Modification of a Disulfide Bond |
| title_sort | minimizing mitogenic potency of insulin analogues through modification of a disulfide bond |
| topic | insulin dicarba insulin insulin receptor biased signalling agonists mitogenic extracellular-signal-regulated kinase (ERK) |
| url | https://www.frontiersin.org/articles/10.3389/fendo.2022.907864/full |
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