PotM: Oligomeric Sarcosine Building Blocks

Our monodisperse Fmoc protected oligomeric sarcosine building blocks with one to eight repetitive units are the ideal building blocks for improved drug delivery strategies. They allow complete control over the synthetic procedure and yield well-defined and reproducible structures, in contrast to conventional polymerization-based preparations with a varying chain length distribution. They may be easily incorporated during any Fmoc-based solid phase peptide synthesis (SPPS) process.

Sarcosine (N-methylglycine, Sar) is a non-proteinogenic amino acid which occurs naturally in the skeletal muscle (hence the name). In polysarcosines, the backbone is formed by N-methyl glycine, which is also the prototype of a molecule class named peptoids. In peptoids, all side chains are attached to the backbone nitrogen atoms (in contrast to the alpha carbon in the case of amino acids). This feature prevents the formation of intramolecular hydrogen bonds like it is the case with amide bonds in peptides, thus peptoids are more flexible. In addition, peptoids and thus polysarcosines are very resistant against enzymatic degradation.

HPLC chromatogram (recent batch) of monodisperse Fmoc-(Sar)₈-OH, indicating a purity of 99%.

Polysarcosines are advantageous in drug delivery: In the development of antibody drug conjugates (ADCs), hydrophobicity (originating e.g., from the drug linker) can be a challenge, as it is limiting the feasible drug to antibody ratio and frequently reduces the drug’s half-life. This effect can be counteracted by adding polysarcosine. In contrast to the frequently used polyethylene glycols (PEGs), which are known to provoke immune responses in some patients and then cause treatments to fail, peptoids and polysarcosines are biocompatible and very well tolerated.

Schematic illustration of a poly(Sarcosine)-modified Antibody-Drug-Conjugate (ADC): For enhanced solubility, poly(Sarcosine) has been added to the linker, which is attached to the antibody via a cysteine reactive maleimide arm. The payload (e.g., a cytotoxic drug) is connected via a self immolative traceless linker and liberated at intracellular pH or by a suitable intracellular enzyme (e.g., Cathepsin B).

In mRNA vaccines, polysarcosines have proven useful as conjugates with lipids, as they allow to control particle size, morphology, and internal structure, so that a high mRNA transfection potency can be achieved. In a study, polysarcosinylated nanocarriers for mRNA excelled by a high protein secretion with a concomitantly low secretion of proinflammatory cytokines, contributing to a favorable safety profile, compared to PEGylated lipid nanoparticles. Furthermore, polysarcosines have been used for transducing proteins into plant cells.

→ For more information about PEG alternatives, see our brochures Polymer Therapeutics! 

References:

Polysarcosine-Functionalized Lipid Nanoparticles for Therapeutic mRNA Delivery; S. Nogueira, A. Schlegel, K. Maxeiner, B. Weber, M. Barz, M. Schroer, C. Blanchet, D. Svergun, S. Ramishetti, D. Peer, P. Langguth, U. Sahin, H. Haas; ACS Appl. Nano Mater. 2020; 3(11): 10634–10645. https://doi.org/10.1021/acsanm.0c01834

Polysarcosine as an Alternative to PEG for Therapeutic Protein Conjugation; Y. Hu, Y. Hou, H. Wang, H. Lu; Bioconjugate Chem. 2018, 29(7): 2232–2238. https://doi.org/10.1021/acs.bioconjchem.8b00237

Monodisperse polysarcosine-based highly-loaded antibody-drug conjugates; W. Viricel, G. Fournet, S. Beaumel, E. Perrial, S. Papot, C. Dumontet, B. Joseph; Chem. Sci. 2019, 10(14): 4048-4053. https://doi.org/10.1039/C9SC00285E

Exatecan Antibody Drug Conjugates Based on a Hydrophilic Polysarcosine Drug-Linker Platform; L. Conilh, G. Fournet, E. Fourmaux, A. Murcia, E.-L. Matera, B. Joseph, C. Dumontet; W. Viricel; Pharmaceuticals 2021; 14(3): 247-233. https://doi.org/10.3390/ph14030247

Preclinical evaluation of somatostatin analogs bearing two macrocyclic chelators for high specific activity labeling with radiometals; D. Storch, J. Schmitt, C. Waldherr, B. Waser, J. Reubi, H. Maecke; Radiochim. Acta. 2007. 95(6): 359-369; https://doi.org/10.1524/ract.2007.95.6.359

Evasion of the Accelerated Blood Clearance Phenomenon by Polysarcosine Coating of Liposomes; K. Son, M. Ueda, K. Taguchi, T. Maruyama, S. Takeoka, Y. Ito; J Control Release: 2020; 322(10): 209-216. https://doi.org/10.1016/j.jconrel.2020.03.022 

A Synthetic Multidomain Peptide That Drives a Macropinocytosis-Like Mechanism for Cytosolic Transport of Exogenous Proteins into Plants; T. Miyamoto, K. Toyooka, J. Chuah, M. Odahara, M. Higchi-Takeuchi, Y. Goto, Y. Motoda, T. Kigawa, Y. Kodama, K. Numata; JAmChemSoc Au. 2022. 2(1): 223−233. https://doi.org/10.1021/jacsau.1c00504