| Autor: |
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 |
| Jazyk: |
angličtina |
| Rok vydání: |
2020 |
| Předmět: |
|
| Zdroj: |
Frontiers in Chemistry, Vol 8 (2020) |
| Druh dokumentu: |
article |
| ISSN: |
2296-2646 |
| DOI: |
10.3389/fchem.2020.532577 |
| Popis: |
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). |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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