PEPTIDES & PROTEINS


Identification and synthesis of highly complex peptide therapeutics


Complex peptide therapeutics now have a bright future due to progress in synthesis chemistry and technology, as well as in delivery methods. Ralph Schoenleber of Bachem describes how new complex peptide leads are being identified from the company’s Melusine library of natural peptides for HTS, and how these are being developed into new therapeutic products.


eptides represent a highly attractive class of therapeutics due to their high activity and high selectivity, and also because they do not accumulate in organs and have low immunogenicity and low toxicity. They are increasingly finding applications in medical areas such as obesity, diabetes, cancer, Alzheimer’s disease, fertility, cardiovascular disorders and wound healing. Peptide therapeutics accounted for revenues of $15 billion in 2010 compared to $8 billion in 2006, representing a CAGR of 17%. This compares with growth from $0.5 billion in 2006 for RNAi medicines to $0.9 billion in 2010, a CAGR of 19%, and growth from $15 billion to $31 billion from 2006 to 2010 for antibody therapeutics, a CAGR of 20%. For protein-based therapeutics as a whole, growth from 2006 to 2010 was from $65 billion to $95 billion, a CAGR of 20%. First approvals for peptide drugs have grown from just nine in 1980 (two of which were in the USA) to 45 in 2008 (with 24 of these in the USA). Bachem’s peptide therapeutics pipeline comprises 138 development projects and 86 drugs on the market, making a total of 224 products. The company has 40 projects in preclinical development, 41 in Phase 1, 32 in Phase 2 and 25 in Phase 3 clinical development. Bachem supplies a large range of generic


P Drug


Exenatide (Byetta)


Capoten (Captopril)


Integrilin (Eptifibatide)


Ziconotide (Prialt)


Tirofiban (Aggrastat)


Company


Amylin & Eli Lilly


Bristol-Myers- Squibb


COR Therapeutics


Elan Corporation


Medicure Pharma & Merck


November/December 2011 peptide APIs to the pharmaceutical industry.


Identification of new peptide therapeutics


The first stage in identifying new peptide therapeutics is lead finding, where assays, modeling and structure analysis, and the application of technologies such as fermentation and high throughput synthesis, phage display and the screening of synthetic libraries and natural products all contribute to identifying new leads.


Natural products such as animal venoms provide good leads, as these are highly complex mixtures of toxins. For example, the venom of the marine cone snail Conus consors contains more than 1,700 compounds. Venoms contain selective and potent bioactives including proteins (protease and other enzymes); toxins targeting ion channels and receptors; peptides that act as inhibitors, activators or hormones; and a wide range of other compounds such as polyamines, alkaloids, and ionic compounds, among others.


Specific advantages of small peptides and mini-proteins as therapeutics are that they have high specificity for their target; high efficiency due to their high binding affinity; high stability and suitable half-lives; low immunogenicity because of their strong


Species


Heloderma suspectum (Gila monster)


Bothrops jararaca (Brazilian lancehead)


Sistrurus miliarus barbouri (Southeastern pygmy rattlesnake)


Conus magus (Magician’s cone)


Echis carinatus (Saw-scaled viper)


Table 1. Examples of venom-derived drugs. 20 sp2


Disease Type-2 diabetes Hypertension Ischemic stroke Severe chronic pain Angina & infarction


Fully automated synthesizers for small-scale solid phase peptide synthesis.


folding; and low toxicity, as they degrade into amino acids. Another attractive feature is that only small amounts of peptide are required, as the dosage of these drugs is typically very low.


Venoms for lead discovery Toxic animal species are a major source of leads as there are more than 100,000 known such species and therefore more than ten million biomolecules that could be potentially investigated. These molecules have been designed by Nature through millions of years of evolution and are therefore highly potent and selective. Venom bioactives, isolated from natural product libraries, are a rich source of highly structured peptides and this class of compounds represents an important alternative to synthetic libraries and peptides obtained from phage display methods for the identification of actives in the lead finding process. In addition, these peptide toxins are quite stable, so the problem of fast


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