Pharmacological Inhibition of Protein Lipidation

Abstract

Lipid modifications of mammalian proteins are widespread, modifying thousands of targets involved in all aspects of cellular physiology cellular physiology. Broadly, lipidations serve to increase protein hydrophobicity and association with cellular membranes. Often, these modifications are absolutely essential for protein stability and localization, and serve critical roles in dynamic regulation of protein function. A number of lipidated proteins are associated with diseases, including parasite infections, neurological diseases, diabetes, and cancer, suggesting that lipid modifications represent potentially attractive targets for pharmacological intervention. This review briefly describes the various types of posttranslational protein lipid modifications, proteins modified by them, and the enzymatic machinery associated with these. We then discuss several case studies demonstrating successful development of lipidation inhibitors of potential (and more rarely, realized) clinical value. Although this field remains in its infancy, we believe these examples demonstrate the potential utility of targeting protein lipidation as a viable strategy for inhibiting the function of pathogenic proteins.

Keywords: Lipid raft; Membrane binding; Microdomain; Post-translational modification; Protein lipidation; Subcellular localization.

Figure 1. Protein Lipidation and its Pharmacological Inhibition

(A) N-Palmitoylation of Hedgehog (Hh), which is also cholesterylated, can be inhibited by targeting the enzyme Hedgehog acetyl transferase (HhAT) with RUSKI-41. (B) Myristate can reversibly target proteins to membranes via a “myrisotyl switch”. This process can be targeted in pathogenic parasites by inhibiting their N-myristoyl transferase (NMT), e.g. by LGK947. (C) S-palmitoylation is a widespread, reversible lipidation that recruits proteins (e.g. the oncogenes N-/H-ras) to membranes and ordered membrane subdomains known as rafts. Palmitoylation is the only reversible lipid modification: the forward reaction is catalyzed by a family of DHHC palmitoyl transferases (PATs) while depalmitoylation is mediated by one of three known protein thioesterases (APT1/2 and PPT1). PATs are inhibited non-specifically by 2-bromopalmitate (2-BP) while depalmitoylation can be affected by palmostatins. (D) Geranyl-geranylation of the small GTPase Rho is catalyzed by geranyl-geranyl transferases, which are inhibited by GGTI-2Z.