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Document Page 313 residues that have been the main focus of attention hitherto. A key requirement now is to identify those residues that provide the majority of the binding energy and to differentiate these from others whose main role is to stabilize the binding residues in the active conformation. VII. Mimicking The Pharmacophore Significant progress has been made over the past few years in the field of peptide mimetics, although the most successful examples are those where a small peptide ligand or a linear segment of a larger protein has been the target [72–74]. An alternative approach to de novo design is to optimize a lead compound obtained by screening chemical libraries on the basis of a knowledge of the conformation of the polypeptide ligand, as in the case of the endothelin receptor antagonist SB 209670 [75]. The task of mimicking a pharmacophore is simplified where the contributing residues are contiguous in the amino acid sequence. This is not the case in the anthopleurins, with residues from at least four different regions of the sequence contributing to affinity. In charybdotoxin the essential residues come from two or three regions of the sequence, depending on which potassium channel is considered, while in growth hormone, binding site I is comprised of residues from three different regions of the protein and site II from two regions. Mimicking the pharmacophore of the anthopleurins therefore represents a task at least as challenging as those presented by these two examples. Strategies for achieving this goal include de novo design, conformationally directed data base searching and screening chemical libraries (synthetic and naturally occurring) for leads, which could then be optimized on the basis of our knowledge of the structure. Our approach is based on the first two of these. Initial attempts to mimic the pharmacophore of AP-A were based on linear and disulfide-cyclized versions of the Arg14-containing loop [76]. At that time, our level of understanding of the pharmacophore was inadequate and it is clear in retrospect that not enough of the key elements were present. Nevertheless, conformational analysis of these peptides by NMR was useful in showing that they retained several elements of local structure observed in the corresponding region of the native protein, thereby emphasizing the independence of this loop from the rest of the structure in solution. VIII. Conclusions In this chapter I have attempted to summarize the current state of our understanding of the structure and structure-function relationships of the type 1 sea http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_313.html [4/5/2004 5:24:04 PM]
Document Page 314 anemone toxins and to indicate how the favorable cardiotonic properties of the anthopleurins might be mimicked in a low molecular weight analog. Progress in defining the cardiotonic pharmacophore has been hampered by difficulties in determining high-resolution structures of the anthopleurins in solution due to the presence of multiple conformers, and by uncertainties concerning the exact location of some of the key residues in the Arg14 loop. Both of these problems would have been alleviated by isotopic labeling of the molecules in a high-yield expression system, which would have allowed for better definition of the structures in solution. The question of how the structure in solution might change upon binding to the sodium channel remains open and is particularly relevant to residues in the Arg14-containing loop. Conformationally constrained analogs of the ligand offer one means of addressing this problem. The definitive solution would be provided by a high-resolution structure for the sodium channel, determined by x-ray or electron crystallography, but this will not be available in the near future. In the meantime, the approach of complementary mutagenesis (of both ligand and receptor), which has been very informative in defining the charybdotoxin-potassium channel interface [68,77], can be employed to produce a crude model of the binding site. Once a lead compound is obtained, further development will almost certainly be required to optimize properties such as bioavailability and stability in vivo. A key requirement will also be good selectivity for the cardiac over other sodium channels, but the results of mutagenesis studies carried out so far on the anthopleurins suggest that this should be achievable. Lead compounds will also have to be rigorously evaluated in terms of their effects on cardiac arrhythmias to ensure that they ameliorate rather than exacerbate this problem, especially in the failing heart. Finally, the possibility that the beneficial effects of positive inotropes in vivo may be the result of inotropic and noninotropic activities [6] would need to be evaluated for mimetics of the anthopleurins. These requirements notwithstanding, there is good reason to be optimistic that a mimetic of the anthopleurins can be developed and that it may have significant benefits in the treatment of congestive heart failure. Acknowledgments I am grateful to all the colleagues who have contributed to our sea anemone toxin work over the years, and, in particular, to Steve Monks, Paul Pallaghy, and Jane Tudor for assistance with the figures and for helpful discussions. I also thank Ken Blumenthal for communicating results prior to publication. Note Added in Proof Since completion of this chapter, two additional papers on site-directed mutations of anthopleurin-B have been published. In the first (Khera PK, Blumenthal http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_314.html [4/5/2004 5:24:06 PM]
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