Synthesis of Novel Arginine Building Blocks with Increased Lipophilicity Compatible with Solid-Phase Peptide Synthesis

Overview

Journal Molecules

Publisher MDPI

Specialty Biology

Date 2023 Dec 9

PMID 38067510

Authors

Mladena Glavas

Agata Gitlin-Domagalska

Natalia Ptaszynska

Dominika Starego

Sylwia Freza

Dawid Debowski

Aleksandra Helbik-Maciejewska

Anna Legowska

Chaim Gilon

Krzysztof Rolka

Affiliations

Soon will be listed here.

Abstract

Arginine, due to the guanidine moiety, increases peptides' hydrophilicity and enables interactions with charged molecules, but at the same time, its presence in a peptide chain might reduce its permeability through biological membranes. This might be resolved by temporary coverage of the peptide charge by lipophilic, enzyme-sensitive alkoxycarbonyl groups. Unfortunately, such a modification of a guanidine moiety has not been reported to date and turned out to be challenging. Here, we present a new, optimized strategy to obtain arginine building blocks with increased lipophilicity that were successfully utilized in the solid-phase peptide synthesis of novel arginine vasopressin prodrugs.

Citing Articles

PIEZO2 Proton Affinity and Availability May Also Regulate Mechanical Pain Sensitivity, Drive Central Sensitization and Neurodegeneration.

Sonkodi B Int J Mol Sci. 2025; 26(3).

PMID: 39941012 PMC: 11818069. DOI: 10.3390/ijms26031246.

References

Schug K, Lindner W . Noncovalent binding between guanidinium and anionic groups: focus on biological- and synthetic-based arginine/guanidinium interactions with phosph[on]ate and sulf[on]ate residues. Chem Rev. 2005; 105(1):67-114. DOI: 10.1021/cr040603j. View

Santana A, Francisco C, Suarez E, Gonzalez C . Synthesis of guanidines from azides: a general and straightforward methodology in carbohydrate chemistry. J Org Chem. 2010; 75(15):5371-4. DOI: 10.1021/jo100876r. View

Bionda N, Cudic P . Solid-phase guanidinylation of peptidyl amines compatible with standard Fmoc-chemistry: formation of monosubstituted guanidines. Methods Mol Biol. 2013; 1081:151-65. DOI: 10.1007/978-1-62703-652-8_10. View

Rader A, Weinmuller M, Reichart F, Schumacher-Klinger A, Merzbach S, Gilon C . Orally Active Peptides: Is There a Magic Bullet?. Angew Chem Int Ed Engl. 2018; 57(44):14414-14438. DOI: 10.1002/anie.201807298. View

Blech S, Ebner T, Ludwig-Schwellinger E, Stangier J, Roth W . The metabolism and disposition of the oral direct thrombin inhibitor, dabigatran, in humans. Drug Metab Dispos. 2007; 36(2):386-99. DOI: 10.1124/dmd.107.019083. View

Gallivan J, Dougherty D . Cation-pi interactions in structural biology. Proc Natl Acad Sci U S A. 1999; 96(17):9459-64. PMC: 22230. DOI: 10.1073/pnas.96.17.9459. View

Burley S, Petsko G . Amino-aromatic interactions in proteins. FEBS Lett. 1986; 203(2):139-43. DOI: 10.1016/0014-5793(86)80730-x. View

Kaiser E, Colescott R, Bossinger C, Cook P . Color test for detection of free terminal amino groups in the solid-phase synthesis of peptides. Anal Biochem. 1970; 34(2):595-8. DOI: 10.1016/0003-2697(70)90146-6. View

Siddiqui F, Qureshi A . Dabigatran etexilate, a new oral direct thrombin inhibitor, for stroke prevention in patients with atrial fibrillation. Expert Opin Pharmacother. 2010; 11(8):1403-11. DOI: 10.1517/14656566.2010.482931. View

10.

Kurasaki H, Nagaya A, Kobayashi Y, Matsuda A, Matsumoto M, Morimoto K . Isostearyl Mixed Anhydrides for the Preparation of -Methylated Peptides Using -Terminally Unprotected -Methylamino Acids. Org Lett. 2020; 22(20):8039-8043. DOI: 10.1021/acs.orglett.0c02984. View

11.

Berlinck R . Natural guanidine derivatives. Nat Prod Rep. 1996; 13(5):377-409. DOI: 10.1039/np9961300377. View

12.

Wang D, Zou L, Jin Q, Hou J, Ge G, Yang L . Human carboxylesterases: a comprehensive review. Acta Pharm Sin B. 2018; 8(5):699-712. PMC: 6146386. DOI: 10.1016/j.apsb.2018.05.005. View

13.

Lenci E, Trabocchi A . Peptidomimetic toolbox for drug discovery. Chem Soc Rev. 2020; 49(11):3262-3277. DOI: 10.1039/d0cs00102c. View

14.

Ghosh A, Brindisi M . Organic carbamates in drug design and medicinal chemistry. J Med Chem. 2015; 58(7):2895-940. PMC: 4393377. DOI: 10.1021/jm501371s. View

15.

Yang Y, Sweeney W, Schneider K, Chait B, Tam J . Two-step selective formation of three disulfide bridges in the synthesis of the C-terminal epidermal growth factor-like domain in human blood coagulation factor IX. Protein Sci. 1994; 3(8):1267-75. PMC: 2142922. DOI: 10.1002/pro.5560030813. View

16.

Vojkovsky T . Detection of secondary amines on solid phase. Pept Res. 1995; 8(4):236-7. View

17.

Weinmuller M, Rechenmacher F, Kiran Marelli U, Reichart F, Kapp T, Rader A . Overcoming the Lack of Oral Availability of Cyclic Hexapeptides: Design of a Selective and Orally Available Ligand for the Integrin αvβ3. Angew Chem Int Ed Engl. 2017; 56(51):16405-16409. DOI: 10.1002/anie.201709709. View

18.

Kamioka S, Shimazu S, Doi T, Takahashi T . Combinatorial synthesis of RGD model cyclic peptides utilizing a palladium-catalyzed carbonylative macrolactamization on a polymer support. J Comb Chem. 2008; 10(5):681-90. DOI: 10.1021/cc800089m. View

19.

Ayele T, Knutson S, Ellipilli S, Hwang H, Heemstra J . Fluorogenic Photoaffinity Labeling of Proteins in Living Cells. Bioconjug Chem. 2019; 30(5):1309-1313. PMC: 6630177. DOI: 10.1021/acs.bioconjchem.9b00203. View

20.

Yang J, Wang C, Yao C, Chen C, Hu Y, He G . Site-Specific Incorporation of Multiple Thioamide Substitutions into a Peptide Backbone via Solid Phase Peptide Synthesis. J Org Chem. 2019; 85(3):1484-1494. DOI: 10.1021/acs.joc.9b02486. View