Explore chapters and articles related to this topic
Synthetic Approaches to Inhibitors of Isoprenoid Biosynthesis
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Pedro Merino, Loredana Maiuolo, Ignacio Delso, Vincenzo Algieri, Antonio De Nino, Tomas Tejero
Protein prenylation, in particular farnesylation and geranylgeranylation, is one of the essential post-translational protein modifications in the eukaryote in which protein prenyltransferases catalyze the transfer of FPP or GGPP to cysteine residues located in conserved prenylation target motifs at the C-terminus of the protein substrate (Clarke, 1992; Merino et al., 2017). This post-translational modification is required for the proper membrane localization and biological function of numerous proteins (Hancock et al., 1989; Kitten and Nigg, 1991; Zhang and Casey, 1996).
The YPT Protein Family in Yeast
Published in Juan Carlos Lacal, Frank McCormick, The ras Superfamily of GTPases, 2017
Warren A. Kibbe, Ludger Hengst, Dieter Gallwitz
Most of the mammalian Rab proteins and all of the yeast Ypt proteins currently known terminate with either two cysteines or with a CysXCys motif (Figure 5). There is increasing evidence that the members of the Ypt/Rab family are modified by geranylgeranylation and that individual transferases are composed of two subunits.39,78-81 Interestingly, the BET2 gene product initially identified to be required for ER-to-Golgi transport in yeast exhibits structural homology to Dprl/Ramlp, one of the subunits of the S. cerevisiae farnesyl transferase. BET2 is required for membrane attachment both of Ypt1p and Sec4p,39 suggesting that it encodes a subunit of a Ypt protein modification enzyme, presumably a geranylgeranyl transferase.
RAS Signaling in Melanoma Development and Prevention
Published in Sanjiv S. Agarwala, Vernon K. Sondak, Melanoma, 2008
There is a strong rationale for statin use as a melanoma chemoprevention agent (12). Data indicate that statin effects on melanoma development appear to be principally via inhibiting geranylgeranylation of Rho and other small G-proteins and less by inhibiting farnesylation of RAS. RhoA and RhoC are known to be widely expressed in human melanoma and have been implicated in causing melanoma metastases. Overexpressed RhoA and RhoC must be geranylgeranylated before melanoma reaches its full invasive potential. In pre-clinical models, lovastatin induced caspase-dependent apoptosis in multiple human melanoma cell lines via a geranylation-specific mechanism (47). The statin atorvastatin, at doses used in treating hypercholesterolemia, could revert the metastatic phenotype in human melanoma cells expressing RhoC (48).
Progeria: a perspective on potential drug targets and treatment strategies
Published in Expert Opinion on Therapeutic Targets, 2022
Ignacio Benedicto, Xue Chen, Martin O Bergo, Vicente Andrés
Additional strategies to treat progeria were based on the idea that progerin and prelamin A, like K-RAS, might undergo alternative prenylation by protein geranylgeranyltransferase type I (GGTase-I) when FTase is inhibited by FTIs [4]. In line with this idea, bone density was partially preserved, and survival increased in progeroid Zmpste24–/– mice upon treatment with statins and aminobisphosphonates, which inhibit both the farnesylation and the geranylgeranylation of progerin/prelamin A [28]. However, the results of a single-arm triple therapy trial revealed no additional benefit of combining lonafarnib with pravastatin and zoledronate compared with lonafarnib monotherapy [29]. The idea that statins and bisphosphonates inhibit prenylation is based on the exposure of cultured cells to high drug doses, which reduce and even block prenylation of certain substrates in this setting. However, there is little or no robust evidence that these classes of drugs inhibit either farnesylation or geranylgeranylation in human tissues in vivo. It is also possible that progerin contributes to HGPS pathogenesis due in part to the lack of 50 amino acids in its C-terminus compared to normal lamin A, an alteration that is not expected to be corrected by FTIs and geranylgeranylation inhibitors.
A patent review of bisphosphonates in treating bone disease
Published in Expert Opinion on Therapeutic Patents, 2019
Based on the patent review, there are still ongoing efforts to develop new analogs of NBPs, and certainly, there is still room for improvement with respect to limiting toxicities such as esophageal irritation, nephrotoxicity and osteonecrosis of the jaw. However, perhaps more intriguing are the efforts to either modify the NBPs to alter biodistribution patterns or to develop novel BP-delivery methods in order to exploit the direct anticancer activities of this class of drugs. While FDPS inhibitors globally inhibit prenylation (i.e. both farnesylation and geranylgeranylation), the predominant effects of these agents as anticancer drugs appear related to disruption of protein geranylgeranylation. Along those lines, the development of specific GGDPS or GGTase II inhibitors represents more specific approaches to disrupt geranylgeranylation. As noted above, the majority of the reported GGTase II inhibitors are heterocyclic carboxyphosphonates and whether the more potent of these agents have sufficient systemic exposure to be effective anticancer agents is currently unknown. The isoprenoid triazole BP-based inhibitors of GGDPS clearly have substantial and prolonged tissue distribution [85,86], highlighting the impact of modifications to a core heterocycle BP structure on bone affinity and systemic distribution. Further studies are needed with both the GGDPS and GGTase II inhibitors to determine whether these agents could have potential as bone-directed therapies and/or systemic therapies targeting malignancies or other diseases outside of the bone.
Pro-inflammatory and pro-resolving mechanisms in the immunopathology of arteriovenous fistula maturation
Published in Expert Review of Cardiovascular Therapy, 2019
Mohan Satish, Palanikumar Gunasekar, Devendra K. Agrawal
As noted with the pro-inflammatory mechanisms, animal trials have offered mechanistic insight and new targets towards the pro-resolution and outward remodeling efforts associated with AVF maturation. For example, the role of NO is further understood with direct evidence that the mRNA expression of endothelial nitric oxide synthase (eNOS) is increased in relation to reduced venous wall thickness in a mouse AVF model [70]. This finding was found to be temporally regulated with increased eNOS expression noted particularly at postoperative day-7 and returning to baseline on postoperative day-21. Understanding this therapeutically, as reviewed by Sugimoto et al. [71], NIH can also be targeted via the Rho/Rho-kinase pathway (negative regulator of eNOS), with Rho-kinase inhibitors, L-arginine, and statins implicated in animal trials through these means [71–75]. Particularly to note, with pleiotropic effects on the vascular system including suppression of cell proliferation, statins have been shown to enhance eNOS activation through the negative modulation of the Rho/Rho-kinase pathway via geranylgeranylation of Rho, thus inactivating Rho-kinase [76]. Geranylgeranylation of Rho (lipid modification) is important for its membrane translocation to activate Rho-kinase and to downregulate eNOS [75]. Outside of the considerations of eNOS, statins have also been shown to decrease the inflammatory response to promote outward remodeling (increased venous outflow area) and prolong AVF patency in a murine model [77].