Drug Discovery Today: Technologies

Vol. 6, No. 1–4 2009

Editors-in-Chief Kelvin Lam – Harvard University, USA Henk Timmerman – Vrije Universiteit, The Netherlands DRUG DISCOVERY



Non-protein therapeutics


Non-protein therapeutics Peter Timmerman Pepscan Therapeutics B.V., Zuidersluisweg 2, Lelystad, The Netherlands. Email: [email protected]

The world around us is chock-full of drugs. Or better call them ‘chemicals with potential drug-like properties’. Nature provides by far the most abundant and diverse library of such chemical compounds. Literally every single species on this planet, such as plants, trees, animals, bacteria and viruses, utilizes its unique biochemical transformation pathways to produce zillions of different chemical structures (DNA, RNA, proteins, peptides, carbohydrates, complex multi(macro)cyclic compounds, among others) with the most outstanding and diverse properties and biological effects, used to either heat, drive, protect, or make species survive in the spectacular environment that life is confronting us with. In theory, all these compounds are potential leads for future drugs, or provide a good starting point for their design or development, either on a structural basis or because of the unique properties they display. Dozens of such compounds originating from nature already made it finally to the market as a commercial drug. The classical example is aspirin. Its pain relieving properties were already reported by the Chinese and Egyptians as early as 2000 BC, even though these early inhabitants used a slightly different formulation (i.e. willow-leaf extracts) than is available nowadays. Other examples include doxorubicin (bacterial product), taxol (isolated from the Pacific Yew tree), or enfuvirtide (trade name FuzeonTM), the first peptidic HIVfusion inhibitor whose structure was derived from the HIV-1 fusion machinery. My personal favorite on this list is the natural compound resveratrol, found in the skin of red grapes and the constituent of red wine that is held responsible by many people for its health-stimulating effect. But by far most promising in this respect is the anticipated cancer-preventive and cancer-killing effect of this non-toxic chemotherapeuticum, which is currently under investigation in more than a dozen clinical trials in humans. 1740-6749/$ ß 2010 Elsevier Ltd. All rights reserved.

DOI: 10.1016/j.ddtec.2010.06.001

This issue of ‘Drug Discovery Today: Technologies’ is centered around (non-protein) drugs and drug development, thereby taking the chemists view as a starting point. Apart from reviewing established classes of drugs and drug perspectives, it takes a deeper look into novel (bio)chemical technologies and how these can be used to transform compounds from different sources (peptides, carbohydrates, among others) into lead products with potential drug-like characteristics that may play a leading role in future drug research. Five articles highlight several of these technologies that are currently under development in various laboratories around the world. Some of these articles involve common drug approaches, like small-molecule inhibitors (SMIs), while others hint on totally novel and therefore less well-established approaches to get hold on the diseased process.

Peter Timmerman, Ph.D., is Chief Technology Officer (CTO) at the pharmaceutical company Pepscan Therapeutics B.V. He is inventor of the CLIPSTM technology, a proprietary technology used to restrict the peptides conformation and thus supports to adopt a native, protein-like conformation. Furthermore, he drives further advances in protein mimicry technology for the development of therapeutic antibodies and/or peptides. He holds a special chair, created by ‘het Genootschap voor Natuur-, Genees-, en Heelkunde’, as professor in Protein Mimetic Chemistry at the Faculty of Science of Amsterdam University. Timmerman has a strong background in chemistry and supramolecular chemistry. He obtained a Ph.D. (summa cum laude) from Twente University with Prof. David Reinhoudt. He was recipient of the 1995 Backer prize for the best thesis in Organic Chemistry. He is (co-)author of over 80 scientific papers and 10 patents. e1

Drug Discovery Today: Technologies | Non-protein therapeutics

The first article by Huib Ovaa and Jacques Neefjes basically covers past and present developments in the field of SMI drugs in cancer therapy. SMIs have dominated the field of drug development for decades, in particular because of their ready availability via traditional chemical synthesis. While the classical non-selective DNA-targeting SMIs (cyclophosphamide, methotrexate, cis-platinum, among others) exhibit severe side-effects in patients, the more recent drugs target much more specifically those proteins that are (more or less) selectively overexpressed in tumor cells. Examples include the family of kinases (BCL-Abl, EML4-ALK), tyrosine kinases (e.g. EGFR), proteases (MMP-family) and GTPases (RAS), and also the more recent targets (PARP, HDAC) will be discussed. Development of therapeutic peptides is a rapidly growing business, some of which have reached a market size of more than one billion US dollars. Despite this, there are still serious limitations towards successful development for many of them. Cyclization in general has proven a fruitful method to create more stable peptide analogues with improved pharmacodynamic properties. The article by Moll, Kuipers, de Vries, Bosma and Rink describes a biological technology for the chemical stabilization of (therapeutic) peptides that uses lantibiotic enzymes for the insertion of thioether bridges in peptides. This emerging technology is chemo-, regio- and stereospecific and has huge potential for the development of a large number of novel, highly effective peptide drugs. Peptides mimicking the binding sites of the HIV-protein(s) to the host cell receptors are discussed in the third article by Kalle Moebius and Jutta Eichler. More than 25 years after the discovery of this pathogenic retrovirus there is still no



Vol. 6, No. 1–4 2009

effective vaccine for HIV. Peptides derived from both the structural and functional HIV-proteins provide an excellent starting point for the design of novel and more effective therapeutic and preventive drugs, being among others virus-entry inhibitors as well as immunogens for neutralizing antibody generation. Recent advances in the design and synthesis of HIV-derived peptide mimics are being discussed. The article by Roland Pieters describes the multivalent presentation of carbohydrate ligands as a novel approach in therapeutic development of protein inhibitors. This approach is expected to have great potential, regarding the fact that nature itself has evolved carbohydrates to act in a multivalent fashion to reach biologically relevant potency levels. Despite excellent perspectives, the real breakthrough will depend on the ability to overcome some of the challenges ahead, like bioavailability and clearance issues. The final article by Hansen, Ruizendaal, Lowik and van Hest reviews the state-of-the-art for switchable peptides, a class of compounds that received increasing interest since the discovery that structural rearrangements in proteins are at the heart of diseases like Alzheimer and Creutzfeldt Jacob. Switching in peptides can be initiated by various triggers including light, temperature, pH, solvent polarity, light, changes in redox-potential, or the addition of metal ions. Knowing the exact mechanisms behind conformational transitions in peptides and proteins might bring therapeutic solutions for these diseases one step closer. With best wishes, Peter Timmerman

Non-protein therapeutics.

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