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European Biopharmaceutical Review

Optimised Therapeutic Peptides - From Sequence to Drug

 

BENEFITS AND LIMITATIONS OF THERAPEUTIC PEPTIDES

Over the last 10 years, many synthetic peptide-based drug products have entered the market as therapeutic agents. Peptides that are finally approved as drugs, such as Fuzeon (Roche), demonstrate the enormous potential that peptides have. Currently, many peptide-based drugs are in clinical or registration phases.

Screening current research literature, there are certainly many peptides that have potential biological activity and could be used as drugs. However, most of them never make it to the early stages of development: only 1.5 per cent of drug candidates will find their way from target identification to approval (1). This is mainly due to their inherent instability/degradability in biological systems, and the unfavourable pharmacokinetic properties of the class.

A rate of 1.5 per cent is high compared to the success of small drugs, but still does not reflect the enormous advances in peptide chemistry and purification of the last decades. This review summarises the exciting potential of the entire field of peptide-drugs, and shows how stateof-the-art peptide engineering can overcome the class limitations of peptides in many cases.

OBJECTIVES OF PEPTIDE OPTIMISATION

The major incentive for the modification of peptides is their potential for major market share in blockbuster indications (such as Affymax: Hematide and Roche: Enfuvirtide). However, the body presents many barriers to the entry of peptides. Peptides do not usually cross biological membranes readily; they are metabolised by proteolytic enzymes and are rapidly excreted through the liver and kidneys.

As a consequence, many natural peptides suffer from low bioavailability and a short biological half-life. Besides the issue of proteolytic instability, there is also the problem of structural instability. Peptides are much smaller than proteins and, for this reason, are structurally less stable, due to their smaller number of intramolecular interactions. Besides improvement in protease resistance, peptides can also need structural stabilisation measures, such as helical constraints, in order to end up with a reasonable specificity and affinity. The primary objective of pharmacological peptide optimisation is to develop analogues that can overcome the problems and barriers related to peptides, while retaining or even enhancing selective activity, usually based on a thorough understanding of the structure-activity relationship. This design-based strategy of peptide optimisation – which is nothing but a high-tech engineering approach –


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Dr Udo Haberl is Director of Drug Design at AplaGen GmbH. He obtained a PhD from the University of Bonn, specialising in theoretical organic chemistry and the development of anti-cancer drugs. He has developed molecular modelling software and worked at the University of Notre Dame (US) and at various biotech companies, where he gained more than 10 years’ experience in the design of pharmaceutical drugs. At AplaGen, he is focusing on design and optimisation of peptide sequences, linker structures and new technologies for peptide stabilisation.

Dr Andreas Rybka is Director of Peptide Chemistry at AplaGen GmbH. He obtained a PhD from the University of Bochum, specialising in the synthesis and conformational analysis (NMR, molecular modelling) of peptides. Andreas has 10 years’ experience in the synthesis, purification and structural analysis of peptides and proteins. At AplaGen, he focuses on the synthesis and purification of peptides and new technologies for peptide synthesis.

Prof Dr Hans-Georg Frank is CEO and co-founder of AplaGen GmbH. He is a physician, and obtained his PhD/MD from the Free University of Berlin. He worked at the Free University of Berlin and the University of Technology in Aachen, Germany, where he focused on embryology, developmental biology and oncological topics. Besides working as an academic scientist, he has also managed clinical studies at Sandoz AG in Nürnberg, Germany. During his academic career, he was awarded large grants from The Rockefeller Foundation and WHO, as well as from the German Research Council, and has published more than 50 articles in peer-reviewed journals. He was appointed Professor at the University of Technology in Aachen.

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Udo Haberl
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Andreas Rybka
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Hans-Georg Frank
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