@article { WOS:000592220600001, title = {Cyclizing Painkillers: Development of Backbone-Cyclic TAPS Analogs}, journal = {FRONTIERS IN CHEMISTRY}, volume = {8}, year = {2020}, note = {[[{"fid":"259082","view_mode":"default","type":"media","attributes":{"style":"width: 250px; height: 125px;","alt":"wer","class":"img-responsive media-element file-default "}}]] }, month = {NOV 12}, 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 mu 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).\ 


}, issn = {2296-2646}, doi = {10.3389/fchem.2020.532577}, author = {Alaa Talhami and Swed, Avi and Hess, Shmuel and Ovadia, Oded and Greenberg, Sarit and Schumacher-Klinger, Adi and Rosenthal, David and Deborah E. Shalev and Mattan Hurevich and Lazarovici, Philip and Amnon Hoffman and Gilon, Chaim} }