Data_Sheet_1_Cyclizing Painkillers: Development of Backbone-Cyclic TAPS Analogs.PDF (1.3 MB)

Data_Sheet_1_Cyclizing Painkillers: Development of Backbone-Cyclic TAPS Analogs.PDF

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posted on 12.11.2020, 05:26 by 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

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).