In collaboration with Professor Barry S. Cooperman (also a member of this department), we are interested in the design and synthesis of non-peptide peptidomimetics as inhibitors of mammalian ribonucleotide reductase (mRR), an enzyme that converts nucleotides into deoxynucleotides, which are ultimately precursors to the building blocks of DNA. Due to this crucial role that mRR plays in the synthesis and regulation of DNA, mRR is a rational target for cancer chemotherapeutics. Currently we are looking at scaffolds modeled around a linear heptapeptide, denoted as P7 (Ac-FTLDADF), whose trNOE structure bound to mR1, one of two major subunits (the other being mR2) of mRR, has been deduced to possess a reverse turn as shown below. Since enzyme activity is totally dependent on the association of mR1 and mR2, P7, which corresponds to the C-terminus of mR2, inhibits enzyme activity by binding competitively with mR2 to mR1. From these data we have recently synthesized two other inhibitors of mRR: 1) a cyclic heptapeptide (cyc-P7), which actually binds more tightly to mR1 than P7; and 2) a tetrahydropyran-based scaffold that does inhibit mRR but is about 20 times less active than P7. Investigation into designing new scaffolds for the purpose of identifying stronger inhibitors is currently underway.