Cyclizing Painkillers: Development of Backbone-Cyclic TAPS Analogs

Alaa Talhami, Avi Swed, Shmuel Hess, Oded Ovadia, Sarit Greenberg, Adi Schumacher-Klinger, David Rosenthal, Deborah E. Shalev, Mattan Hurevich, Philip Lazarovici, Amnon Hoffman, Chaim Gilon*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Painkillers are commonly used medications. Native peptide painkillers suffer from various pharmacological disadvantages, while small molecule painkillers like morphine are highly addictive. We present a general approach aimed to use backbone-cyclization to develop a peptidomimetic painkiller. Backbone-cyclization was applied to transform the linear peptide Tyr-Arg-Phe-Sar (TAPS) into an active backbone-cyclic peptide with improved drug properties. We designed and synthesized a focused backbone-cyclic TAPS library with conformational diversity, in which the members of the library have the generic name TAPS c(n-m) where n and m represent the lengths of the alkyl chains on the nitrogens of Gly and Arg, respectively. We used a combined screening approach to evaluate the pharmacological properties and the potency of the TAPS c(n-m) library. We focused on an in vivo active compound, TAPS c(2-6), which is metabolically stable and has the potential to become a peripheral painkiller being a full μ opioid receptor functional agonist. To prepare a large quantity of TAPS c(2-6), we optimized the conditions of the on-resin reductive alkylation step to increase the efficiency of its SPPS. NMR was used to determine the solution conformation of the peptide lead TAPS c(2-6).

Original languageAmerican English
Article number532577
JournalFrontiers in Chemistry
Volume8
DOIs
StatePublished - 12 Nov 2020

Bibliographical note

Publisher Copyright:
© Copyright © 2020 Talhami, Swed, Hess, Ovadia, Greenberg, Schumacher-Klinger, Rosenthal, Shalev, Hurevich, Lazarovici, Hoffman and Gilon.

Keywords

  • TAPS
  • backbone cyclization
  • cycloscan
  • peripheral painkiller
  • reductive alkylation

Fingerprint

Dive into the research topics of 'Cyclizing Painkillers: Development of Backbone-Cyclic TAPS Analogs'. Together they form a unique fingerprint.

Cite this