Peptide-derived compounds

Figure 14.8. Thermograms for the volatilization of peptide-derived compounds in freeze-dried rhizodeposits leached from a soil cropped with maize after a daytime and a nighttime growth period and thermogram for the volatilization of L-glutamic acid. Reprinted from Leinweber, P., Jandl, G., Baum, C., Eckhardt, K.-U., and Kandeler, E. (2008). Stability and composition of soil organic matter control respiration and soil enzyme activities. Soil Biology and Biochemistry 40,1496-1505, with permission from Elsevier.

The five dipeptides listed below were treated as follows (a) The dipeptide was reacted exhaustively with FDNB. (b) The reaction was then acidified and extracted with ether, (c) The ether phase from this extraction was dried down, resuspended in 0.5 ml of 6 N HC1, and heated at 110°C for 12 hr. (d) 1 ml of water and 2 ml of ether were then added to the sample. For each of the dipeptides listed below, list the peptide-derived compounds that you would expect to find in the final ether phase and the final aqueous phase following the series of four treatments described above. 

The discovery of peptide-based substrate-mimicking HIVPI was directed towards the synthesis of substrate analogs in which the scissile bond was replaced by a non-cleavable isostere with tetrahedral geometry that could mimic the tetrahedral transition-state of the proteolytic reaction. Thus, several inhibitors with hydroxyethylene or hydroxyethylamine isostere replacement were prepared to bind with the enzyme as shown in Fig. 3a [31]. However, the clinical development of peptide-derived compounds was hindered by their poor pharmacokinetics, including low oral bioavailability, rapid excretion and complex (expensive) synthesis [44,45]. Therefore, recently more... 

A group of peptide derivatives such as peptide arginals and boronic acid peptide derivatives belong to another class of reversible thrombin inhibitors. One such inhibitor is PPACK (D-Phe-Pro-Arg chloromethyl ketone), which functions as a powerful irreversible thrombin inhibitor by alkylating the histidine residue at the catalytic site of thrombin (58). It, however, is unstable in neutral solution, as it undergoes cyclization and inactivation. However, the D-methyl derivative of D-Phe-Pro-Arg-H (D-Mephe-Pro-Arg-H) called efegatran, with a molecular mass of 515 Da, is a stable selective reversible inhibitor of thrombin with a K. of approximately 100 nM. The basic amino terminus in this compound is responsible for promoting the specificity toward thrombin (63). 

The past 3 years have seen tremendous advances in both the design of Cat K inhibitors and in our understanding of the effect of Cat K inhibition on bone remodeling. The structural diversity of Cat K inhibitors has expanded considerably from simple peptidomimetics to non-peptidic derivatives and even non-covalent inhibitors. The potency, selectivity and pharmacokinetic properties of key compounds are very attractive and seem well-suited to further development. The disclosure of clinical validation of the effect of Cat K inhibition on bone mineral density, plus the provocative data suggesting a decoupling of bone resorption and bone formation provides a compelling framework for further development of Cat K inhibitors for the treatment of osteoporosis. 

Protein Kinase Inhibitors Pseudosubstrate-based peptide inhibitors, 201, 287 utilization of the inhibitor protein of adenosine cyclic monophosphate-dependent protein kinase, and peptides derived from it, as tools to study adenosine cyclic monophosphate-mediated cellular processes, 201, 304 use of sphingosine as inhibitor of protein kinase C, 201, 316 properties and use of H-series compounds as protein kinase inhibitors, 201, 328 use and specificity of staurosporine, UCN-01, and calphostin C as protein kinase inhibitors, 201, 340 inhibition of protein-tyrosine kinases by tyrphostins, 201, 347 use and specificity of genistein as inhibitor of protein-tyrosine kinases, 201, 362 use and selectivity of herbimycin a as inhibitor of protein-tyrosine kinases,... 

Robust peptide-derived approaches aim to identify a small drug-like molecule to mimic the peptide interactions. The primary peptide molecule is considered in these approaches as a tool compound to demonstrate that small molecules can compete with a given interaction. A variety of chemical, 3D structural and molecular modeling approaches are used to validate the essential 3D pharmacophore model which in turn is the basis for the design of the mimics. The chemical approaches include in addition to N- and C-terminal truncations a variety of positional scanning methods. Using alanine scans one can identify the key pharmacophore points D-amino-acid or proline scans allow stabilization of (i-turn structures cyclic scans bias the peptide or portions of the peptide in a particular conformation (a-helix, (i-turn and so on) other scans, like N-methyl-amino-acid scans and amide-bond-replacement (depsi-peptides) scans aim to improve the ADME properties." ... 

Great amount of marine fish species have been identified with potential nutraceutical and medicinal values. Consequently, a number of bioactive compounds have been identified including fish muscle proteins, peptides, collagen and gelatin, fish oil, fish bone. Bioactive peptides derived from various fish muscle proteins have shown various biological activities including antihypertensive, antibacterial, anticoagulant, anti-inflammatory, and antioxidant activities, and hence they may be a potential material for biomedical and... 

---