IGF2 Peptide-Based LYTACs for Targeted Degradation of Extracellular and Transmembrane Proteins
Lysosome-targeting chimeras (LYTACs) have recently been developed to facilitate the lysosomal degradation of specific extracellular and transmembrane molecular targets. However, the LYTAC particles described to date are based on glycopeptide conjugates, which are difficult to prepare and produce on...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-11-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/28/22/7519 |
| _version_ | 1797458229695873024 |
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| author | Michał Mikitiuk Jan Barczyński Przemysław Bielski Marcelino Arciniega Urszula Tyrcha Aleksandra Hec Andrea D. Lipińska Michał Rychłowski Tad A. Holak Tomasz Sitar |
| author_facet | Michał Mikitiuk Jan Barczyński Przemysław Bielski Marcelino Arciniega Urszula Tyrcha Aleksandra Hec Andrea D. Lipińska Michał Rychłowski Tad A. Holak Tomasz Sitar |
| author_sort | Michał Mikitiuk |
| collection | DOAJ |
| description | Lysosome-targeting chimeras (LYTACs) have recently been developed to facilitate the lysosomal degradation of specific extracellular and transmembrane molecular targets. However, the LYTAC particles described to date are based on glycopeptide conjugates, which are difficult to prepare and produce on a large scale. Here, we report on the development of pure protein LYTACs based on the non-glycosylated IGF2 peptides, which can be readily produced in virtually any facility capable of monoclonal antibody production. These chimeras utilize the IGF2R/CI-M6PR pathway for lysosomal shuttling and, in our illustrative example, target programmed death ligand 1 (PD-L1), eliciting physiological effects analogous to immune checkpoint blockade. Results from in vitro assays significantly exceed the effects of anti-PD-L1 antibodies alone. |
| first_indexed | 2024-03-09T16:34:06Z |
| format | Article |
| id | doaj.art-3953071d4d124e7382acdaaa72b81cb4 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-09T16:34:06Z |
| publishDate | 2023-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-3953071d4d124e7382acdaaa72b81cb42023-11-24T14:58:05ZengMDPI AGMolecules1420-30492023-11-012822751910.3390/molecules28227519IGF2 Peptide-Based LYTACs for Targeted Degradation of Extracellular and Transmembrane ProteinsMichał Mikitiuk0Jan Barczyński1Przemysław Bielski2Marcelino Arciniega3Urszula Tyrcha4Aleksandra Hec5Andrea D. Lipińska6Michał Rychłowski7Tad A. Holak8Tomasz Sitar9Recepton Sp. z o.o., Trzy Lipy 3, 80-172 Gdańsk, PolandRecepton Sp. z o.o., Trzy Lipy 3, 80-172 Gdańsk, PolandRecepton Sp. z o.o., Trzy Lipy 3, 80-172 Gdańsk, PolandRecepton Sp. z o.o., Trzy Lipy 3, 80-172 Gdańsk, PolandRecepton Sp. z o.o., Trzy Lipy 3, 80-172 Gdańsk, PolandRecepton Sp. z o.o., Trzy Lipy 3, 80-172 Gdańsk, PolandLaboratory of Virus Molecular Biology, Intercollegiate Faculty of Biotechnology, University of Gdańsk and Medical University of Gdańsk, 80-307 Gdańsk, PolandLaboratory of Virus Molecular Biology, Intercollegiate Faculty of Biotechnology, University of Gdańsk and Medical University of Gdańsk, 80-307 Gdańsk, PolandDepartment of Organic Chemistry, Faculty of Chemistry, Jagiellonian University, Gronostajowa 2, 30-387 Krakow, PolandRecepton Sp. z o.o., Trzy Lipy 3, 80-172 Gdańsk, PolandLysosome-targeting chimeras (LYTACs) have recently been developed to facilitate the lysosomal degradation of specific extracellular and transmembrane molecular targets. However, the LYTAC particles described to date are based on glycopeptide conjugates, which are difficult to prepare and produce on a large scale. Here, we report on the development of pure protein LYTACs based on the non-glycosylated IGF2 peptides, which can be readily produced in virtually any facility capable of monoclonal antibody production. These chimeras utilize the IGF2R/CI-M6PR pathway for lysosomal shuttling and, in our illustrative example, target programmed death ligand 1 (PD-L1), eliciting physiological effects analogous to immune checkpoint blockade. Results from in vitro assays significantly exceed the effects of anti-PD-L1 antibodies alone.https://www.mdpi.com/1420-3049/28/22/7519LYTACtargeted protein degradationPD-1PD-L1immune checkpoint blockade |
| spellingShingle | Michał Mikitiuk Jan Barczyński Przemysław Bielski Marcelino Arciniega Urszula Tyrcha Aleksandra Hec Andrea D. Lipińska Michał Rychłowski Tad A. Holak Tomasz Sitar IGF2 Peptide-Based LYTACs for Targeted Degradation of Extracellular and Transmembrane Proteins Molecules LYTAC targeted protein degradation PD-1 PD-L1 immune checkpoint blockade |
| title | IGF2 Peptide-Based LYTACs for Targeted Degradation of Extracellular and Transmembrane Proteins |
| title_full | IGF2 Peptide-Based LYTACs for Targeted Degradation of Extracellular and Transmembrane Proteins |
| title_fullStr | IGF2 Peptide-Based LYTACs for Targeted Degradation of Extracellular and Transmembrane Proteins |
| title_full_unstemmed | IGF2 Peptide-Based LYTACs for Targeted Degradation of Extracellular and Transmembrane Proteins |
| title_short | IGF2 Peptide-Based LYTACs for Targeted Degradation of Extracellular and Transmembrane Proteins |
| title_sort | igf2 peptide based lytacs for targeted degradation of extracellular and transmembrane proteins |
| topic | LYTAC targeted protein degradation PD-1 PD-L1 immune checkpoint blockade |
| url | https://www.mdpi.com/1420-3049/28/22/7519 |
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