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El. knyga: Application of Peptide-Based Prodrug Chemistry in Drug Development

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Macromolecular (specifically peptide-based) drugs could potentially be highly effective medicines. However they have a relatively short duration of action and variable therapeutic index. An example of such a peptide is Glucagon-like Peptide I which could potentially be used as a revolutionary drug for diabetes. This is because it stimulates insulin only when the blood glucose level is high thereby reducing the risk of hypoglycemia (a significant disadvantage of using insulin is that an insulin overdose is the single most potent cause of life-threatening hypoglycemia). However its short duration of action (half-life of 2 minutes in plasma) precludes its therapeutic use.

In this volume, the use of novel therapeutics like GLP1 as an alternative to tradition insulin-based drugs in diabetes is described. Application of Peptide-Based Prodrug Chemistry in Drug Development elucidates the traditional concept of prodrugs as specialized non-toxic protective groups used in a transient manner to alter or to eliminate certain limiting properties in the parent small molecule (IUPAC definition). It goes on to provide insight into how prodrugs of peptides (with GLP1 as an example) could be appropriately used to extend the biological half life, broaden the therapeutic index of macromolecules and improve the pharmacodynamics of such drugs.  Author explains the logic behind designing peptide prodrugs, synthetic procedures and bioassays to examine the conversion of the prodrug to the drug under therapeutic conditions. The prodrugs described slowly convert to the parent drug at physiological conditions of 37C and pH 7.2 driven by their inherent chemical instability without the need of any enzymatic cleavage. The diketopiperazine and diketomorpholine (DKP and DMP) strategies for prodrug conversion are demonstrated in detail with special emphasis on the chemical flexibility that it offers to develop prodrugs with variable time actions.

This book will be of usefulto chemists, biochemists, medicinal chemists, biologists and people in the medical profession (doctors). It may be used in undergraduate classes but will certainly help post-graduate students and advanced professionals.

The author is grateful to Prof. Richard DiMarchi (Standiford H. Cox Professor of Chemistry and the Linda & Jack Gill Chair in Biomolecular Sciences at Indiana University) for valuable suggestions. The foreword for the book has been written by Prof. Jean Martinez, (Legion d'Honneur awarded by the French Republic; Professor of Chemistry and Medicinal Chemistry of the University of Montpellier, France; and Chairman of European Peptide Society, 2002-2010).
1 Introduction
1(14)
1.1 Diabetes
1(2)
1.2 Insulin
3(2)
1.3 Glucagon-Likepeptide 1 (GLP 1)
5(4)
1.4 Prodrug
9(2)
References
11(4)
2 Application of Prodrug Chemistry to GLP-1
15(8)
2.1 Introduction
15(6)
References
21(2)
3 Experimental Procedures
23(8)
3.1 Peptide Synthesis (Boc Amino Acids/HF Cleavage)
24(1)
3.2 Peptide Synthesis (Fmoc Amino Acids/HF Cleavage)
25(1)
3.3 Depsipeptide Synthesis (Amino Ester Formation)
25(1)
3.4 N-Terminal Hydroxyl Peptide Synthesis (α-Hydroxyl-N Terminal Extension)
26(1)
3.5 HF Treatment of the Peptidyl-Resin
27(1)
3.6 Analysis Using Mass Spectrometry
28(1)
3.7 High Pressure Liquid Chromatography (HPLC) Analysis
28(1)
3.8 Preparative Purification Using HPLC
29(1)
3.9 Bioassay Experimental Design: Luciferase-Based Reporter Gene Assay for cAMP Detection
29(1)
References
29(2)
4 Characterization of Prodrugs
31(22)
4.1 GLP-Oxyntomodulin
31(2)
4.2 Adding Dipeptides to the N-Terminus
33(3)
4.3 Adding Dipeptides to the N-Terminus of F7, GLP(8-36)-CEX
36(3)
4.4 Depsipeptides and Esters
39(1)
4.5 Adding Dipeptides to the OH Terminus of HO-F7, GLP(H-36)-CEX
39(11)
4.6 Bioassays of Selected Longer Acting Prodrug Candidates
50(1)
References
51(2)
5 Conclusion
53(8)
References
59(2)
Appendix I Schematic Synthesis of Longer Acting Prodrugs 61(4)
Appendix II Structure of Peptides in Table A.1 65(4)
Appendix III Structure of Peptides in Table A.2 69(2)
Appendix IV Structure of Peptides in Table A.3 71(2)
Appendix V Structure of Peptides in Table A.4 73(2)
Appendix VI Structure of Peptides in Table A.5 75(4)
Appendix VII Structure of Peptides in Table A.6 79(4)
Appendix VIII Acylation of HO-His7, GLP(8-37) 83(4)
Appendix IX A Note on Nomenclature 87(2)
About the Author 89
Arnab De, M.A, M.Phil , is currently a PhD candidate at Columbia University Medical Center. He completed his undergraduate education in Presidency College, Calcutta, India before coming to the Unites States for his higher education. He came to Indiana University, Bloomington where he worked with Prof. Richard DiMarchi (Standiford H. Cox Professor of Chemistry and the Linda & Jack Gill Chair in Biomolecular Sciences) to develop peptide-based prodrugs as therapeutics for diabetes. The work with Prof. DiMarchi resulted in two patents (licensed by Marcadia Biotech, recently acquired by Roche) and multiple publications in peer reviewed journals. He presented his findings in the American Peptide Symposium2009 and received the Young Investigators Award. He subsequently came to Columbia University where he is developing transgenic mice to serve as potential models for autoimmune diseases. He was invited by Carolyn J Honour (Editorial Director, Biomedicine at Springer) to write this bookin the Springer Brief series. The foreword has been written by Prof. Jean Martinez (Legion d'Honneur awarded by the French Republic and Chairman of European Peptide Society, 2002-2010).
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