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PotM: Guanidino-Proline as rigid Arginine mimic
PotM: Guanidino-Proline as rigid Arginine mimic
Published on 18/05/2021
The site-directed replacement of one amino acid within a peptide sequence or protein allows to determine the role of this individual element for peptide/protein function and to investigate its effect on receptor interactions. Especially the incorporation of structurally closely related, but conformationally different derivatives provides a high level of functional resolution. Finally, such structure-activity data allow the fine-tuning e.g. of peptide drugs for optimized receptor binding and maximized efficiency and activity.
For the methodical study of Arginine containing peptides, our portfolio includes two guandinylated Proline derivatives, trans- and cis-ProGU. The strong basic guanidino group of Arginine, which is almost always protonated at physiological pH, plays a pivotal role in molecular recognition processes. It is crucial for hydrogen bonding as well as ionic interactions with binding partners. In contrast to the rather flexible guanidino group of Arginine, trans-ProGU and cis-ProGU represent constrained mimics. In both Proline derivatives, the guanidinium moiety is directly attached to the gamma carbon. Thus, the positively charged moiety is rather localized, which allows to study the topographic importance of the guanidinium group for receptor interaction and peptide activity.
The constrained Arginine mimics trans-ProGU and cis-ProGU.
As an example, the introduction of a guanidinylated Proline in Arg-rich peptides resulted in 2.5- to 15-fold higher cellular uptake and approximately 100-fold more efficient pDNA transfection efficiencies compared to R9 peptides. Within our portfolio, we offer two guanidinylated Proline derivatives, which are listed at the end of this article under “related products”. Those Fmoc-protected guanidino-Pbf derivatives can easily be introduced as building blocks during peptide synthesis.
Interested in other Arginine derivatives? Check-out our webshop or inquire for a custom synthesis.
References:
- Structural Development of Cell-Penetrating Peptides Containing Cationic Proline Derivatives; H. Kobayashi, T. Misawa, M. Oba, N. Hirata, Y. Kanda, M. Tanaka, K. Matsuno, Y. Demizu; Chem. Pharm. Bulletin 2018; 66(5): 575-580. https://doi.org/10.1248/cpb.c18-00079.
- Effect of Preorganized Charge-Display on the Cell-Penetrating Properties of Cationic Peptides; Y. A. Nagel, P. S. Raschle, H. Wennemers; Angew. Chem. Int. Ed. 2017; 56(1): 122-126. https://doi.org/10.1002/anie.201607649.
- Plasmid DNA delivery by arginine-rich cell-penetrating peptides containing unnatural amino acids; T. Kato, H. Yamashita, T. Misawa, K. Nishida, M. Kurihara, M. Tanaka, Y. Demizu, M. Oba; Bioorg. Med. Chem. 2016; 24(12): 2681-2687. https://doi.org/10.1016/j.bmc.2016.04.031.
- Substitution of Arginine with Proline and Proline Derivatives in Melanocyte-Stimulating Hormones Leads to Selectivity for Human Melanocortin 4 Receptor; H. Qu, M. Cai, A. V. Mayorov, P. Grieco, M. Zingsheim, D. Trivedi, V. J. Hruby; J. Med. Chem. 2009; 52(12): 3627-3635. https://doi.org/10.1021/jm801300c.
- Rational Design of a-Conotoxin Analogues Targeting a7 Nicotinic Acetylcholine Receptors; C. Armishaw, A. A. Jensen, T. Balle, R. J. Clark, K. Harpsøe, C. Skonberg, T. Liljefors, K. Strømgaard; J. Biol. Chem. 2009; 284(14): 9498-9512. https://doi.org/10.1074/jbc.M806136200.
- Synthesis of Proteins Containing Modified Arginine Residues; A. K. Choudhury, S. Y. Golovine, L. M. Dedkova, S. M. Hecht; Biochem. 2007; 46(13): 406-4076. https://doi.org/10.1021/bi062042r.
- Practical and Efficient Synthesis of Orthogonally Protected Constrained 4-Guanidinoprolines; M. Tamaki, G. Han, V. J. Hruby; J. Org. Chem. 2001; 66(3): 1038-1042. https://doi.org/10.1021/jo005626m.
- Synthesis of Alanine and Proline Amino Acids with Amino or Guanidinium Substitution on the Side Chain; Z. Zhang, A. V. Aerschot, C. Hendrix, R. Busson, F. David, P. Sandra, P. Herdewijn; Tetrahedron 2000; 56(16): 2513-2522. https://doi.org/10.1016/S0040-4020(00)00123-X.
- Conformationally restricted arginine analogs; T. R. Webb, C. Eigenbrot; J. Org. Chem. 1991; 56(9): 3009-3016. https://doi.org/10.1021/jo00009a016.
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