IJOC  Vol.2 No.1 , March 2012
Lipopeptides for the Fragment-Based Pharmaceutics Design
Abstract: This paper describes the synthesis of peptide fragments for use in a new type of combinatorial discovery technology, in which the building blocks are brought together by non-covalent interactions, rather than direct chemical bonding. The building blocks of interest—in this case different amino acids—are converted to amphiphiles by attachment to lipid tails. The amphiphiles, when mixed together in aqueous phase, are designed so that they aggregate spontaneously to form micelles. The building blocks form the headgroups of each of the amphiphiles, and these headgroups cover the surface of the micelle in a dynamic close-packed fluid mosaic array. These building blocks come together so closely that two- or three-dimensional structures are created on the surface of the micelles, and these can be screened in biological assays to find out which combination of building blocks is able to elicit a biological response. Lipopeptides consisting of two residues of lipoamino acid and other amino acids moieties have been designed, synthesized, characterized and the ability of these constructs to form supra-molecular assemblies is demonstrated.
Cite this paper: Z. M. Ziora, N. Wimmer, R. New, M. Skwarczynski and I. Toth, "Lipopeptides for the Fragment-Based Pharmaceutics Design," International Journal of Organic Chemistry, Vol. 2 No. 1, 2012, pp. 75-81. doi: 10.4236/ijoc.2012.21013.

[1]   H. Kubinyi, “Chemogenomics” In: H. Kubinyi, Ed., Comprehensive Medicinal Chemistry II, Volume 3: Drug Discoveries Technolgies, Elsevier, New York, 2006, pp 921-937.

[2]   P. Seneci, “Combinatorial Chemistry,” In: H. Kubinyi, Ed., Comprehensive Medicinal Chemistry II, Volume 3: Drug Discoveries Technolgies, Elsevier, New York, 2006, pp 697-760.

[3]   S. Nayak, D. Panda and J. Sahoo, “Nanosuspension: A Novel Drug Delivery System,” Journal of Pharmacy Reserach, Vol. 3, No. 2, 2010, pp. 241-246.

[4]   V. Shankarananth and K. Rajasekhar, “Combinatorial Chemistry: A Review,” Drug Invention Today, Vol. 2, No. 1, 2010, pp. 49-52.

[5]   V. J. Hruby and J. Vagner, “High Throughput Synthesis of Peptides and Peptidomimetics,” Chimica Oggi, Vol. 24, No. 4, 2006, pp. 18-21.

[6]   H. A. Behanna, J. J. M. Donners, A. C. Gordon and S. I. Stupp, “Coassembly of Amphiphiles with Opposite Peptide Polarities into Nanofibers” Journal of American Chemical Society, Vol. 127, No. 4, 2005, pp. 1193-1200. doi:10.1021/ja044863u

[7]   E. Kokkoli, A. Mardilovich, A. Wedekind, E. L. Rexeisen, A. Garg and J. A. Craig, “Self-Assembly and Applications of Biomimetic and Bioactive Peptide-Amphiphiles,” Soft Matter, Vol. 2, No. 3, 2006, pp. 1015-1024. doi:10.1039/b608929a

[8]   W. A. Gibbons, R. A. Hughes, M. Charalambous, M. Christodoulou, A. Szeto, A. E. Aulabaugh, P. Mascagni and I. Toth, “Lipidic Peptides. VIII. Cellular Uptake Studies of Lipidic Amino Acid, Its Oligomers and Highly Lipophilic Drug Conjugates,” Liebigs Annalen der Chemie, Vol. 79, No. 1-3, 1990, pp. 1175-1183. doi:10.1002/jlac.1990199001215

[9]   R. New and I. Toth, “Epitopes Formed by Non-Covalent Association of Conjugates,” PCT Int. Appl. 2001, WO 2001001140.

[10]   C. C. Yang and R. B. Merrifield, “The Beta-Phenacyl Ester as a Temporary Protecting Group to Minimize Cyclic Imide Formation During Subsequent Treatment of Aspartyl Peptides with HF,” Journal of Organic Chemistry, Vol. 41, No. 6, 1976, pp. 1032-1041. doi:10.1021/jo00868a025

[11]   I. Schwope, C. F. Bleczinski and C. Richert,“Synthesis of 3',5'-Dipeptidyl Oligonucleotides,” Journal of Organic Chemistry, Vol. 64, No. 13, 1999, pp. 4749-4761. doi:10.1021/jo990036d

[12]   A. S. Abdelrahim, Z. M. Ziora, J. A. Bergeon, A. R. Moss and I. Toth, “Design and Synthesis of a Series of Novel, Cationic Liposaccharide Derivatives as Potential Pene- tration Enhancers for Oral Drug Delivery,” Tetrahedron, Vol. 65, No. 45, 2009, pp. 9436-9442. doi:10.1016/j.tet.2009.08.072

[13]   Z. M. Ziora, N. Wimmer, R. New, M. Skwarczynski and I. Toth, “Synthesis of Glycolipo-peptidic Building Blocks for Carbohydrate Receptor Discovery,” Carbohydate Research, Vol. 346, No. 12, 2011, pp. 1439-1444. doi:10.1016/j.carres.2011.03.019

[14]   M. Skwarczynski, B. H. Parhiz, F. Soltani, S. Srinivasan, K. A. Kamaruzaman, I-C. Lin and I. Toth, “Lipid Peptide Core Nanoparticles as Multivalent Vaccine Candidates against Streptococcus Pyogenes,” Australian Journal of Chemistry, Vol. 65, 2012, pp. 35-39. doi:10.1071/CH11292.

[15]   M. Zaman, M. Skwarczynski, J. M. Malcolm, C. N. Urbani, Z. F. Jia, M. R. Batzloff, M. F. Good, M. J. Monteiro and I. Toth “Self-Adjuvanting Polyacrylic Nano- Particulate Delivery System for Group A Streptococcus (GAS) Vaccine,” Nanomedicine: Nanotechnology, Biology and Medicine, Vol. 7, No. 2, 2011, pp. 168-173. doi:10.1016/j.nano.2010.10.002

[16]   M. Skwarczynski, M. Zaman, C. N. Urbani, I. C. Lin, Z. F. Jia, M. R. Batzloff, M. F. Good, M. J. Monteiro and I. Toth, “Polyacrylate Dendrimer Nanoparticles: A Self-Adjuvanting Vaccine Delivery System,” Angewandte Chemie-International Edition, Vol. 49, No. 33, 2010, pp. 5742-5745. doi:10.1002/anie.201002221

[17]   I. Toth, M. Danton, N. Flinn and W. A. Gibbons, “Combined Adjuvant and Carrier System for Enhancing Synthetic Peptides Immunogenicity Utilising Lipidic Amino Acids,” Tetrahedron Letter, Vol. 34, 1993, pp. 3925-3928. doi:10.1016/S0040-4039(00)79265-3

[18]   M. Skwarczynski and I. Toth, “Lipid-Core-Peptide System for Self-Adjuvanting Synthetic Vaccine Delivery,” In: S. S. Mark, Ed., Bioconjugation Proto- cols: Strategies and Methods, 2nd Edition, Humana Press Inc., Totowa, 2011, pp. 297-308. doi:10.1007/978-1-61779-151-2_18