On-target activity

There are many examples of the introduction of fluorine enhancing on-target activity and these only represent a small number. Many more will be exemplified in the remaining sections of this chapter. 

Key words siRNA, Argonaute proteins, siRNA off-target activity, siRNA on-target activity, siRNA design, siRNA modifications... 

Taken together, siRNAs can induce pronounced off-target effects and therefore it is important to design siRNAs and perform siRNA-based experiments in a way that reduces off- and increases on-target activities. 

Many metabolites retain activity from the parent drug, that is, on-target activity. Selected examples of marketed drugs, the major metabolite of each, and the percentage activity of the metabolite are shown in Table 8.1. 

Figure 9.39 Effects of replacing an amide with a trifluoroethylamine isostere on target activity and P-gp efflux as determined in a cellular transport assay. References 6 and 7 are from the original publication. (Reprinted with permission from Moore, K.P., et al. Strategies toward improving the brain penetration of macrocyclic tertiary carbinamine BACE-1 inhibitors. Bioorg. Med. Chem. Lett. 2007 17, 5831-5835, copyright 2007, Elsevier).

Compound optimization, to screen a series of therapeutic diug candidates to find the compounds that are most specific for the target protein and those that cause unintended effects, i.e. improved understanding of the molecular mode of action including structure-activity relationships for on-target versus off-target effects... 

The concept of drug development is based on the findings that retinoid receptors (RARs and RXRs) offer a new approach by targeting different genes depending on the activated retinoid receptor complexes. The multiplicity of these retinoid signaling pathways affords potential for therapeutic opportunity as well as retinoid therapy associated undesired side effects. It is possible that the indiscriminate activation of all pathways by nonspecific retinoid ligands could lead to unacceptable side effects so that any enhanced efficacy would be obtained at the cost of enhanced toxicity. 

Cytokines are small, short-lived proteins and important mediators of local intercellular communication. They play a key role in integrating responses to a variety of stimuli in immune and inflammatory processes. By binding their cognate receptors on target cells in their immediate vicinity, these molecules participate in many important biological activities including cell proliferation, activation, death and differentiation. In... 

Ubiquitin tags proteins for protein degradation. The ubiquitination requires three different enzymatic activities, a ubiquitin-activating enzyme (El), a ubiquitin-conjugating enzyme (E2 or Ubc) and a ubiquitin ligase (E3). The action of all three enzymes leads to the establishment of a poly-ubiquitin chain on target proteins which are then recognized and proteolyzed by the 26S proteasome. 

Insulin and other growth factors result in the phosphorylation of BP-1 at five unique sites. Phosphorylation of BP-1 results in its dissociation from 4E, and it cannot rebind until critical sites are dephosphorylated. The protein kinase responsible has not been identified, but it appears to be different from the one that phos-phorylates 4E. A kinase in the mammalian target of rapamycin (mTOR) pathway, perhaps mTOR itself, is involved. These effects on the activation of 4E explain in part how insuhn causes a marked posttranscriptional... 

Figure 42-13. Structure of bovine preproparathyroid hormone. Arrows indicate sites cieaved by processing enzymes in the parathyroid giand (1-5) and in the iiver after secretion of the hormone (4-5). The bioiogicaiiy active region of the moiecuie is fianked by sequence not required for activity on target receptors. (Slightly modified and reproduced, with permission, from Habener JF Recent advances in parathyroid hormone research. Clin Biochem 1981 14 223.)...

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