Homologous proteins species selection

The Animal Species Selection section of the ICH document also refers to the use of homologous proteins and transgenic animals that express the human receptor. One example of a development program that relied on surrogates for safety assessment is that of infliximab [8], Many of the challenges of these models are acknowledged in this section. Animal models of disease are also discussed and can be used with strong scientific rationale. 

MAO A and B differ in primary structure and in substrate specificity [5,7]. The two isozymes, located on the mitochondrial outer membranes, have 70% homology in peptide sequence and share common mechanistic details. It is now recognized that these are different proteins encoded by different genes, but probably derived from a common ancestral gene. Crystal structures for both MAO A and B complexes with inhibitors have recently been reported [8]. Serotonin is selectively oxidized by MAO A, whereas benzylamine and 2-phenylethylamine are selective substrates for MAO B. Dopamine, norepinephrine, epinephrine, trypt-amine, and tyramine are oxidized by both MAO A and B in most species [9]. In addition, MAO A is more sensitive to inhibition by clorgyline (1), whereas MAO B is inhibited by low concentrations of L-deprenyl ((f )-( )-deprenyl) (2) [5,6cj. Development of inhibitors that are selective for each isozyme has been an extremely active area of medicinal chemistry [8]. 

Figure 4.16 Homology of -casein from a selection of species indicates residues identical at the same position for all species + indicates similar residues, - an inserted space. I indicates the N terminus of the mature protein (from Holt and Sawyer, 1993).

A. G. Pavlovsky, D. F. Ortwine. Effect of species differences on stromelysin-1 (MMP-3) inhibitor potency. An explanation of inhibitor selectivity using homology modeling and chimeric proteins. J Biol Chem. 1999, 274, 24881-24887. 

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