Protein synthetic agents

Yin H, Hamilton AD. (2005) Strategies for targeting protein-protein interactions with synthetic agents. Angew. Chem. Int. Ed. 44 4130 163. 

Ethambutol is a synthetic agent and not related to any of the other tuberculostatics. Its mechanism of action is not well understood but in actively dividing mycobacteria it appears to be an inhibitor of mycobacterial RNA synthesis. It also has effects on bacterial phosphate metabolism and on polyamine synthesis. It is an bacteriostatic agent and its main function in combination therapy is to delay the occurrence of resistance, mainly against isoniazid and rifampicin. It is well absorbed after oral administration. It is widely distributed, except to the CNS. Protein binding is about 20-30%. It is mainly excreted unchanged in the bile and urine with an elimination half-life of 3 h. Ethambutol is concentrated in erythrocytes and thus provides a depot for continuous release. 

However, even erythrocyte AChE measurements cannot be expected to be a perfect surrogate for the nervous tissue enzyme this is because pharmacokinetic factors may result in differential access of the inhibitor to the red cell and to neural structures. A further consideration is that, where nerve agents react with the enzyme to produce a phosphonylated structure that does not spontaneously reactivate, red cells of mammals lack the protein synthetic capability to synthesize new AChE. By contrast, in nervous tissue, after inhibition by OPs whose enzyme-inhibitor complex with AChE does not readily reactivate, activity may reappear relatively quickly. Thus, Wehner et al (1985) observed approximately 30% recovery after 24 h in di-isopropylfluorophosphate (DFP)-treated mouse CNS reaggregates, which was clearly due to synthesis de novo of AChE. Another consideration in the interpretation of butyrylcholinesterase activity measurements is that the normal range is relatively wide, rendering interpretation in individual patients difficult unless the results of previous estimations in the patient are available (Swami-nathan and Widdop, 2001). 

Olomucine (46), originally isolated from the cotyledons of radish (Raphanus sativus L.A.) provided the natural product model for the synthetic agent roscovitine (47). Olomucine (46) inhibits cyclin-dependent kinases, proteins that play a major role in cell cycle progression. R-Roscovitine is currently in Phase II clinical trials... 

In contrast, the development of synthetic agents that modulate protein-protein interactions is much more demanding even though it is of great therapeutic value. In particular, approaches for the disruption of protein-protein interactions are made more difficult because (a) large... 

Strategies for targeting protein-protein interactions with synthetic agents 05AG(E)4130. 

Another group of important biological targets is peptides and proteins. A variety of medical treatments and medical diagnostics could be developed using synthetic agents that are capable of specific protein or peptide recognition. 

Jain, R. K. Hamilton, A. D. Designing protein denaturants synthetic agents induce cytochrome c unfolding at low concentrations and stoichiometries. Angew. Chem., Int. Ed. 2002,41, 641-643. 

The chloroisocyanurates can be used in the bleaching of cotton, synthetics, and their blends they do, however, attack proteinaceous fibers, such as silk or wool, presumably via active chlorine reaction with the peptide (amide) linkage. However, the chloroisocyanurates can be used as shrink-proofing agents in wool finishing (131), (see Textiles Wool). The same action of chlorine upon proteins contributes to the effectiveness of chloroisocyanurates in automatic dishwashers. 

Oxazolidinones are a new class of synthetic antimicrobial agents, which have activity against many important pathogens, including methicillin-resistant Staphylococcus aureus and others. Oxazolidinones (e.g. linezolid or eperezolid) inhibit bacterial protein synthesis by inhibiting the formation of the 70S initiation complex by binding to the 50S ribosomal subunit close to the interface with the 3OS subunit. 

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