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Phytopharmaceuticals in Cancer Treatment
Published in Prakash Srinivasan Timiri Shanmugam, Understanding Cancer Therapies, 2018
Prince Clarance, Paul Agastian
Fusicoccanes is a family of metabolites from Fusicoccum amygdali and Drechslera gigantean. Cotylenin A is a member of the Fusicoccane family that inhibits the growth of various tumor types both in vitro and in vivo without apparent adverse effects in human xenograft models (Honma et al. 2003). In addition to this, the Fusicocccane family includes fusicoccin A and ophiobolins. Fusicoccin A is an α-D-glucopyranoside of the diterpenoid 5-8-5 ring skeleton. It is the main phytotoxin produced by Fusicoccum amygdali, the causative fungal agent of peach and almond canker (Balli et al. 1964).
Cystic Fibrosis: Proteostatic correctors of CFTR trafficking and alternative therapeutic targets.
Published in Expert Opinion on Therapeutic Targets, 2019
John W. Hanrahan, Yukiko Sato, Graeme W. Carlile, Gregor Jansen, Jason C. Young, David Y. Thomas
Post-translational modifications control chaperone specificity as illustrated by a modification of Hsp70 that is catalyzed by the acetylase ARD1 [77]. Acetylation of Hsp70 on lysine 77 enhances its interaction with the co-chaperone Hop to promote protein folding whereas deacetylation switches its binding to the ubiquitin ligase CHIP. Another potential corrector drug target that mediates post-translational modifications is the ubiquitin ligase RMA1/RNF5 [78]. RMA1/RNF5 acts early during CFTR biogenesis and recognizes when MSD1, NBD1, and the R-domain are misassembled. Silencing RMA1/RNF5 or the ERAD component Derlin-1 (which helps translocate misfolded proteins from the ER) increases F508del-CFTR functional expression by 70–80% in the CFBE cell line [79]. Both the potential of specific E3 ubiquitin ligase inhibitors and the challenges associated with their development have been reviewed [80]. Proof-of-principle for F508del-CFTR rescue by pharmacological inhibitors of RNF5/RMA1 is provided by a recent study that involved virtual screening followed by validation in primary airway cells [81]. The regulatory protein 14-3-3 β belongs to a large family of proteins that bind to phosphorylated polypeptides including the R domain of CFTR [82]. Such binding increases the net flux of CFTR protein through the secretory pathway by reducing its interactions with the COPI machinery, thereby reducing retrograde transport back to the ER from the Golgi [82]. The natural product fusicoccin increases F508del-CFTR correction by enhancing binding of 14-3-3 β dimers to the R-domain of CFTR [83].
Computational approaches for the design of modulators targeting protein-protein interactions
Published in Expert Opinion on Drug Discovery, 2023
Ashfaq Ur Rehman, Beenish Khurshid, Yasir Ali, Salman Rasheed, Abdul Wadood, Ho-Leung Ng, Hai-Feng Chen, Zhiqiang Wei, Ray Luo, Jian Zhang
The 14-3-3 protein family is a particularly intriguing topic for PPI modulation research because it has been discovered to have hundreds of protein-protein interactions. PPIs play a role in a variety of biological processes, including cell cycle regulation, signal transduction, protein trafficking, apoptosis, and cancer [177]. 14-3-3 proteins are also involved in phosphorylation-dependent PPIs, which regulate cell cycle progression, the initiation and maintenance of DNA damage checkpoints [178]. Besides this, 14-3-3 proteins are also involved in the progression of many neuropathological disorders [179,180], bound to tau-tangles and enhancing their aggregation as seen in Alzheimer’s patients [181]. Using small molecules to modify these PPIs is a crucial method for creating new drugs. The literature has reported a variety of natural, semi synthetic and synthetic compounds that perform their physiological functions by stabilizing complexes of their target proteins [182]. Fusicoccin-A (FC-A), a metabolite generated by the fungus Phomopsis amygdali, is an example of a natural stabilizer and was the first stabilizer to be reported for 14-3-3/client PPIs. The plasma membrane H+-ATPase (PMA2) and 14-3-3 complex was discovered to be stabilized by FC-A, with a 90 times increase in the affinity [183]. It was also found to stabilize 14-3-3/cystic fibrosis transmembrane conductance regulator (CFTR) complex that resulted in enhanced delivery to the plasma membrane. By looking at the examples above and many more [180,184], it can be deduced that FC-A might act as a potential chemical tool for investigating the role of 14-3-3 in various pathologies.