Therapeutic
Peptide and Protein Stabilization
The need
Protein and peptides are gaining an ever stronger position in the arsenal of modern medical therapies because they are seen as nature's own solution to medical aberrations and, consequently, should be able to provide effective treatment with the highest level of specificity and the lowest level of deleterious side effects. The growing number of clinical trails with protein and peptide drug candidates has led to predictions that within the foreseeable future all new medicines will be biologicals. Paradoxically, however, our bodies seem to be designed to thwart their widespread application. If they are administered orally, they cannot be adsorbed by the intestine because they are too large; instead they are broken down by digestive enzymes. Its the bodies natural way of providing building blocks for the construction of new cellular structures. Injections are, therefore, the most general route of administration but injections are a burden to the patient and still not a general solution to proteolytic breakdown because the blood also contains enzymes which degrade these molecules before they can be therapeutically effective. The challenge is therefore, two-fold: 1) to stabilize proteins and peptides against proteolytic degradation so that they can circulate longer in the blood and thus achieve an higher level of therapeutic efficacy and, 2) if possible, find a way to get them efficiently across the intestinal membrane in order enable effective oral administration.
The status
We are capable of generating different thioether-containing peptides by our biosynthetic process and have used this approach for bioactive peptides. Incorporating thioether linkages resulted in enhanced stability in vitro. Preclinical studies for one therapeutic peptide, Angiotensin 1-7, showed longer circulation times and an enhanced therapeutic effect when compared with the parent, non-stabilized compound. (Haas, M., Kluskens, L., Kuipers, A., Rink, R., Nelemans, S. and Moll, G. (2008) Cyclic angiotensin analogues. Patent Application WO 2008/018792A2)