Advan. Enzyme Regul. 45 (2005) 112–125 Peptide inhibitors of mammalian ribonucleotide reductase Barry S. Cooperman à , Ying Gao, Chiheng Tan, Ossama B. Kashlan, Jaskiran Kaur Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104-6323, USA Introduction Ribonucleotide reductases (RRs) form a family of allosterically regulated enzymes that catalyze the conversion of ribonucleotides to 2 0 -deoxyribonucleotides and are essential for de novo DNA biosynthesis (Eklund et al., 2001). As such, RR is a well- recognized target for cancer chemotherapeutic and antiviral agents (Weber, 1983; Cory, 1988; Szekeres et al., 1997; Robins, 1999), with activity levels that are more than 100-fold higher in rapidly growing hepatoma cells than in normal liver cells (Weber, 1983). Two compounds are currently in clinical use, targeting either the active site (gemcitabine) (Robins, 1999, van Moorsel et al., 2000) or the stable tyrosyl free radical that is required for enzyme activity (hydroxyurea) (Nocentini, 1996). Mammalian RR (mRR) belongs to Class Ia of the four known classes of RRs. Class Ia RRs accept the four common nucleoside diphosphates (NDPs) as substrates, with enzymatic activity dependent upon the formation of a complex between two different subunits, R1 and R2 (Eklund et al., 2001). The mammalian cell contains one gene product for R1 but two gene products for R2, mR2 and p53R2, which are 80% identical in sequence and functionally similar. The expression of p53R2 is under the control of the tumor suppression protein p53 (Byun et al., 2002). Each R2 contains a stable tyrosyl free radical that is necessary for NDP ARTICLE IN PRESS www.elsevier.com/locate/advenzreg 0065-2571/$ - see front matter r 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.advenzreg.2005.02.012 à Corresponding author. Tel.:+1 215 898 6330; fax: +1 215 898 2037. E-mail address: Cooprman@pobox.upenn.edu (B.S. Cooperman).