Dataset Information

Cyclizing Painkillers: Development of Backbone-Cyclic TAPS Analogs.

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 ? 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).

SUBMITTER: Talhami A

PROVIDER: S-EPMC7689096 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Publications

Cyclizing Painkillers: Development of Backbone-Cyclic TAPS Analogs.

Talhami Alaa A Swed Avi A Hess Shmuel S Ovadia Oded O Greenberg Sarit S Schumacher-Klinger Adi A Rosenthal David D Shalev Deborah E DE Hurevich Mattan M Lazarovici Philip P Hoffman Amnon A Gilon Chaim C

Frontiers in chemistry 20201112

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-c ...[more]

PMID: 33282822

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Project description:Cyclization is commonly employed in efforts to improve the target binding affinity of peptide-based probes and therapeutics. Many structural motifs have been identified at protein-protein interfaces and provide promising targets for inhibitor design using cyclic peptides. Cyclized peptides are generally assumed to be rigidified relative to their linear counterparts. This rigidification potentially pre-organizes the molecules to interact properly with their targets. However, the actual impact of cyclization on, for example, peptide configurational entropy, is currently poorly understood in terms of both its magnitude and molecular-level origins. Moreover, even with thousands of desired structural motifs at hand, it is currently not possible to a priori identify the ones that are most promising to mimic using cyclic peptides nor to select the ideal linker length. Instead, labor-intensive chemical synthesis and experimental characterization of various cyclic peptide designs are required, in hopes of finding one with improved target affinity. Herein, using molecular dynamics simulations of polyglycines, we elucidated how head-to-tail cyclization impacts peptide backbone dihedral entropy and developed a simple strategy to rapidly screen for structures that can be reliably mimicked by preorganized cyclic peptides. As expected, cyclization generally led to a reduction in backbone dihedral entropy; notably, however, this effect was minimal when the length of polyglycines was >9 residues. We also found that the reduction in backbone dihedral entropy upon cyclization of small polyglycine peptides does not result from more restricted distributions of the dihedrals; rather, it was the correlations between specific dihedrals that caused the decrease in configurational entropy in the cyclic peptides. Using our comprehensive cyclo-Gn structural ensembles, we obtained a holistic picture of what conformations are accessible to cyclic peptides. Using "hot loops" recently identified at protein-protein interfaces as an example, we provide clear guidelines for choosing the "easiest" hot loops for cyclic peptides to mimic and for identifying appropriate cyclic peptide lengths. In conclusion, our results provide an understanding of the thermodynamics and structures of this interesting class of molecules. This information should prove particularly useful for designing cyclic peptide inhibitors of protein-protein interactions.

Dataset Information

Cyclizing Painkillers: Development of Backbone-Cyclic TAPS Analogs.

Publications

Cyclizing Painkillers: Development of Backbone-Cyclic TAPS Analogs.

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