Polypeptides, therapeutic

Therapeutics. Therapeutic materials represent a class of polypeptides that are a low volume, high value product. The production system need not be very efficient but the quaHty of the recombinant protein has to be extremely pure (33,34). Thus high cost mammalian production systems can be tolerated. However, some of the therapeutic proteins such as insulin, human growth hormone, interleukins, interferon, and streptokinase are produced microbially. 

Melatonin [73-31-4] C 2H N202 (31) has marked effects on circadian rhythm (11). Novel ligands for melatonin receptors such as (32) (12), C2yH2gN202, have affinities in the range of 10 Af, and have potential use as therapeutic agents in the treatment of the sleep disorders associated with jet lag. Such agents may also be usehil in the treatment of seasonal affective disorder (SAD), the depression associated with the winter months. Histamine (see Histamine and histamine antagonists), adenosine (see Nucleic acids), and neuropeptides such as corticotropin-like intermediate lobe peptide (CLIP) and vasoactive intestinal polypeptide (VIP) have also been reported to have sedative—hypnotic activities (7). 

Therapeutic Function Antitubercular Chemical Name Cyclic polypeptide antibiotic Common Name Caprolin Structural Formula ... 

The promise of the isolation and production of therapeutic polypeptides and proteins demands that for treatment of a chronic disease state an oral delivery system be developed which will protect these valuable agents from the hostile gastric environment. Subsequently, the drugs will have to be completely released in the intestine, preferably in a state that will enhance their rapid dissolution and transport across the gut wall minimizing interaction with intestinal proteases. 

Several pathological self-polymerizing systems have been biophysi-cally characterized sufficiently to permit identification of protein or peptide species that could serve as molecular targets in a structure-activity relationship. These include transthyretin (TTR) [73-76], serum amyloid A protein (SAA) [77], microtubule-associated protein tau [78-80], amylin or islet amyloid polypeptide (IAPP) [81,82], IgG light chain amyloidosis (AL) [83-85], polyglutamine diseases [9,86], a-synuclein [47,48] and the Alzheimer s (3 peptide [87-96]. A variety of A(3 peptide assay systems have been established at Parke-Davis to search for inhibitors of fibril formation that could be therapeutically useful [97]. 

Further improvement of the low detection limit was achieved using stripping voltammetry based on facilitated heparin adsorption and desorption [66], Stripping voltammetry yielded a detection limit of 0.13 U mL 1 in sheep blood plasma, which is lower than therapeutic heparin concentrations (>0.2 U mL-1). A linear response function in the range of 0.2-6 U mL 1 was observed. The authors also found that blood polypeptides and lipids with a mass above 25 000 significantly interfered with heparin detection, perhaps by hindrance of a charge transfer reaction at the interface. 

Many polypeptides undergo covalent modification after (or sometimes during) their ribosomal assembly. The most commonly observed such PTMs are listed in Table 2.7. Such modifications generally influence either the biological activity or the structural stability of the polypeptide. The majority of therapeutic proteins bear some form of PTM. Although glycosylation represents the most common such modification, additional PTMs important in a biopharmaceutical context include carboxylation, hydroxylation, sulfation and amidation these PTMs are now considered further. 

Amidation refers to the replacement of a protein s C-terminal carboxyl group with an amide group (COOH — CONH2). This PTM is usually characteristic of peptides (very short chains of amino acids), as opposed to the longer polypeptides, but one therapeutic polypeptide (salmon calcitonin, Chapter 11) is amidated, and amidation is required for full functional activity. Overall, the function(s) of amidation is not well understood, although in some cases at least it appears to contribute to peptide/polypeptide stability and/or activity. 

Gao, B., Hagenbuch, B., Kullak-Ublick, G.A., Benke, D., Aguzzi, A. and Meier, P. J. (2000) Organic anion-transporting polypeptides mediate transport of opioid peptides across blood-brain barrier. Journal of Pharmacology and Experimental Therapeutics, 294, 73-79. 

Nozawa, T., Imai, K., Nezu, J., Tsuji, A. and Tamai, I. (2004) Functional characterization of pH-sensitive organic anion transporting polypeptide OATP-B in human. Journal of Pharmacology and Experimental Therapeutics, 308,438—445. 

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