AUTHOR=Talhami Alaa , Swed Avi , Hess Shmuel , Ovadia Oded , Greenberg Sarit , Schumacher-Klinger Adi , Rosenthal David , Shalev Deborah E. , Hurevich Mattan , Lazarovici Philip , Hoffman Amnon , Gilon Chaim TITLE=Cyclizing Painkillers: Development of Backbone-Cyclic TAPS Analogs JOURNAL=Frontiers in Chemistry VOLUME=Volume 8 - 2020 YEAR=2020 URL=https://www.frontiersin.org/journals/chemistry/articles/10.3389/fchem.2020.532577 DOI=10.3389/fchem.2020.532577 ISSN=2296-2646 ABSTRACT=Painkillers are commonly used medications. Natural 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 TAPS to an active backbone-cyclic peptide with enhanced pharmacological properties. We designed and synthesized a focused backbone-cyclic TAPS library with conformational diversity. The members of the library have the generic name TAPS c(n-m) where n and m represent the length 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 found an in vivo active compound, TAPS c(2-6), which is metabolically stable and has potential as a peripheral painkiller. 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 determined the bioactive conformations of TAPS c(2-6).