Solid Phase Synthesis of Peptidomimetics

Figure 1. Nerve growth factor (NGF) dimer with the beta-turn regions highlighted

Solid phase SnAr macrocyclizations and related reactions have enabled us to prepare

beta-turn mimics in a library format. Beta-Turns are pivotal to many protein-protein interactions.

We are attempting to prepare and test small molecule mimics of nerve growth factor (NGF).

Functional mimics of this proteins could be useful in treatment of neurodegenerative

diseases including Alzheimer's disease, ALS Lou Gehring's disease, trauma, and of

various forms of cancer. The approach that we are using for to mimic neurotrophis

could also be applied to other proteins that dock with transmembrane receptors.

Figure 2 shows the key macrocyclization step in a synthesis of one peptidomimetic,

and the results of a confomational analysis of one such compound performed

using NMR and computer simulations.

c

Figure 2. a. Key macrocyclization step in a peptidomimetic synthesis. b. Preferred conformation of one such peptidomimetic from NMR and computational studies. c. Our dimerization scheme for forming homo- and hetero-bivalent dimers.

Molecules in which two turn mimics are joined together have the potential for much higher affinity

binding to other proteins than ones that only resemple one hot-spot. Recently we devised a method for

joining monovalent molecules together to form bivalent ones. This method tolerates unprotected side

chains and does not require coupling agents. Yiends in relatively large libraries of bivalent molecules.

Our research initiative is focused on overcoming the logistical problems of doing this.

a

b

Figure3. a. Libraries of bivalent compounds made by combining all available monovalent comounds in all permutations rapidly build up numbers, but tending to waste valuable building blocks exploring unproductive areas of diversity space; whereas, b. an evolving strategy that perseveres only with the monovalent compounds that have shown activity and focuses the libary as it evolves.

Ultimately, we hope to be able to test the concept of "evolving libraries" as outlined in

Figure 3. This avoids the problems of manipulating large numbers of molecules that

would be encountered if a complete library were made and tested (Figure 3a), while

providing a comparable diversity.

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