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).
Highlights
Peptides bearing the pharmacophoric residues necessary for inhibiting protein-protein interactions can induce pharmacologic activity (Pelay-Gimeno et al, 2015)
We developed a short backbonecyclic peptide opioid analog based on the TAPS sequence that combined both selective agonistic activity toward the μ opioid receptor and metabolic stability
We determined the amide nitrogens of the linear parent peptide which are suitable anchors for backbone-to-backbone cyclization
Summary
Peptides bearing the pharmacophoric residues necessary for inhibiting protein-protein interactions can induce pharmacologic activity (Pelay-Gimeno et al, 2015). Backbone cyclization was developed as a general technique for the conversion of peptides or the active region in proteins into drug-leads (Fears et al, 2018; Rubin and Qvit, 2018). It is based on cyclization via the α-nitrogens of the peptide backbone (Figures 1C,D). The advantages of backbone cyclization over other cyclization methods are: (i) The ring does not alter the structure of the pharmacophoric side chains and termini of the linear parent peptide; (ii) Backbone cyclization restricts the conformation
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