Design, Synthesis, and Characterization of Peptide-Based Rab Geranylgeranyl Transferase Inhibitors

Abstract

Rab geranylgeranyl transferase (RabGGTase) catalyzes the attachment of geranylgeranyl isoprenoids to Rab guanine triphosphatases, which are key regulators in vesicular transport. Because geranylgeranylation is required for proper function and overexpression of Rabs has been observed in various cancers, RabGGTase may be a target for novel therapeutics. The development of selective inhibitors is, however, difficult because two related enzymes involved in other cellular processes exist in eukaryotes and because RabGGTase recognizes protein substrates indirectly, resulting in relaxed specificity. We report the synthesis of a peptidic library based on the farnesyl transferase inhibitor pepticinnamin E. Of 469 compounds investigated, several were identified as selective for RabGGTase with low micromolar IC(50) values. The compounds were not generally cytotoxic and inhibited Rab isoprenylation in COS-7 cells. Crystal structure analysis revealed that selective inhibitors interact with a tunnel unique to RabGGTase, implying that this structural motif is an attractive target for improved RabGGTase inhibitors.

Understanding and Exploiting Protein Prenyltransferases

“…76 Recently, the synthesis of a series of novel peptomimic inhibitors selective for RabGGTase was reported 77. 78…”

Structure‐Guided Development of Selective RabGGTase Inhibitors

“…Herein we report the structure‐guided design of selective RabGGTase inhibitors with potent cellular activities. The inhibitors target the RabGGTase‐specific tunnel adjacent to the GGPP binding site (TAG tunnel), which was recently found in a cocrystal structure of an RabGGTase‐peptide‐based inhibitor 8b. Since this TAG tunnel is a unique feature that distinguishes RabGGTase from FTase and GGTase I, it provides a rational molecular basis to achieve selectivity.…”

Development of Selective, Potent RabGGTase Inhibitors

“…One unique feature of RabGGTase is a tunnel adjacent to the GGPP binding site, the so-called TAG tunnel, identified during the evaluation of peptide-based selective RabGGTase inhibitors. 17 The second opportunity to create selective inhibitors is presented by the lipid binding site (LBS). Extensions into or near the LBS were expected to be accommodated in RabGGTase while generating a clash with Trp102 of FTase, an aromatic residue in FTase that is the main determinant of FPP over GGPP selectivity ( Figure 2).…”