Peptidic tool compounds

Figure 1 Non-peptidic tool compounds for the 5 opioid receptor (antagonists).

In conclusion, the investigation of peptidic and non-peptidic tool compounds for the 5 receptor have demonstrated the potential use of 5 agonists and antagonists for a variety of clinical applications, especially for the treatment of pain. Full exploitation of this potential will however only be possible with ideal non-peptidic compounds having high potency, selectivity and, above all, optimal drug metabolism and pharmacodynamic characteristics. 

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." ... 

While no further development of FK 33-824, Biphalin, Important peptidic tool DPDPE or other prominent opioid peptides has been compounds for opioid... 

Table 2 Peptidic opioid receptor tool compounds.

Table 15.5-2 Example of peptidic inhibitors used as tool compounds for studying the p53-hdm2 interaction. The IC50 values were obtained in a competition assay [49], The position of the three key residues Phel9, Trp23, and Leu26 is indicated...

In another study, the carrier protein was replaced by an enzyme compatible solid-phase resin (PEGA), and enzyme-catalyzed cyclization was used to probe substrate specificity. This study demonstrated also that oxo-esters are tolerated as substrates for TE domains, and then-preparation in library format served as an excellent tool for substrate specificity studies, as well as for preparation of cyclized peptides. Figure 13.11 shows how the TycA TE showed selectivity for only residues 1 and 9 (colored in red), and changes at all other residues were tolerated [42]. Hydrogen bonding interactions are shown in green. Several compounds made from this series were shown to demonstrate improved therapeutic indices (with respect to hemolysis) while retaining antimicrobial activity. 

The interest in these peptides and others whose mechanisms of action are not yet so clearly defined is evident from the many recent publications. Since the peptides are not orally active, their role in the treatment of hypertension is uncertain at this point. Their value as diagnostic tools has been established. For example, the use of saralasin in the recognition of angiotensinogenic hypertension in man has been demonstrated (103). Perhaps of greater value will be the role of these compounds and peptides still to come in defining the importance of the renin-angiotensin system in the etiology of hypertension and the control of blood pressure. 

As an alternative approach an adenosine-derived mustard was developed as a PRMT inhibitor by a strategy that was based on the mechanism of the enzyme. This compound is an alkylating agent which is covalently attached to a peptide substrate only upon incubation with PRMTl [80]. It is not very druglike and is more of a chemical tool. 

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,... 

Abstract Piperazines and its congeners, (di)keto piperazines are valuable tools in drug discovery, providing a natural path for the process peptide > peptidomimetic > small molecule also called depeptisation. Moreover, they can provide molecular probes to understand molecular pathways for diseases of unmet medical need. However, in order to better understand the design of such value added compounds, the detailed understanding of scope and limitation of their synthesis as well as their 3D structures and associated physicochemical properties is indispensables. Isocyanide multicomponent reaction (MCR) chemistry provides a prime tool for entering the chemical space of (di)(keto)piperazines since not less then 20 different ways exist to access a diversity of related scaffolds. 

Since ifs infroducfion in fhe lafe 1980s [6], MALDl MS has become one of the most valuable tools for nof only fhe invesfigafion of polymeric biomolecules like peptides, profeins, and oligonucleotides buf also for the analysis of technical polymers, small organic molecules, and low-molecular weight compounds of biological interest like amino acids, lipids, and carbohydrates [7]. 

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