PTEN-5-HT2CR Complex: An Ideal Target for Developing Treatment to Restore the Functioning of 5-HT2CR; An Attempt to Minimize the Development of Antimicrobial Resistance

Date

2018-08

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Abstract

PART I ABSTRACT Serotonin 2C receptor (5-HT2CR) plays an important role in the regulation of neurotransmission disorders and maybe an ideal target to develop treatments for drug addiction. The coupling between the 5-HT2CR and protein phosphatase and tensin homologue (PTEN) limited the activity of the receptor. The disruption of the interaction has been demonstrated to restore the activity of 5-HT2CR. A key fragment (3L4F-F1) of 5-HT2CR can disrupt the interaction between 5-HT2CR and PTEN. To mimic this fragment, an alanine scan was utilized. The results show that Asn(I), Asp, Asn(II), and Arg are the key amino acids for the bioactivity. A β-turn template was synthesized to develop physiologically-stable inhibitors. The β-turn peptidomimetic shows good biological activity and will be utilized to guide the development of future molecules.

PART II ABSTRACT Antimicrobial resistance is a growing public health threat and observed in bacteria that cause common health problems and infections. Aminoacyl-tRNA synthetases (AsRSs) which use a unique two-step mechanism of aminoacylation reaction are ideal targets for antibacterials. AN2690, a benzoxaborole derivative, shows great antibiotic activity by trapping tRNALeu in the editing domain. Inspired by AN2690 and other benzoxaborole derivatives, we designed (S)-3-Aminomethyl-7-(3-hydroxy-propoxy)-3H-benzo[c][1,2]oxaborol-1-ol to block the editing domain. A rationally stable analogue of Leu-AMP intermediate was designed to block the active site. After linking them together, we hope this dimer can target the editing domain and the catalytic domain simultaneously to minimize the development of antimicrobial resistance.

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Keywords

Serotonin receptor, Drug addiction, Protein phosphatase and tensin homologue, Β-turn template, Antimicrobial resistance, Aminoacyl-tRNA synthetases, Benzoxaborole derivative, Editing domain, Active sites

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