Peptide Ligation at High Dilution via Reductive Diselenide-Selenoester Ligation.
Chisholm. Timothy S TS; Kulkarni. Sameer S SS; Hossain. Khondker R KR; Cornelius. Flemming F; Clarke. Ronald J RJ; Payne. Richard J RJ
Key Findings
- A reductive diselenideâselen oester ligation (rDSL) method can join peptide fragments at nanomolar concentrations.
- rDSL avoids the need for solubilityâenhancing tags or templates during synthesis.
- The method was used to synthesize the FDAâapproved lipopeptide tesamorelin and lipidâmodified variants of the membrane protein FXYD1, which affect Naâș/Kâș pump activity.
Practical Outcomes
- For biohackers, this study doesnât provide new dosing guidance or performance benefits for tesamorelin. It mainly offers a new tool for chemists to make peptide drugs more efficiently, which could eventually lower production costs, but thereâs no immediate actionable protocol for users.
Summary
Scientists developed a new chemistry trick that lets them stitch together peptide pieces even when theyâre in very tiny amounts and hard to dissolve. Using this trick, they made the drug tesamorelin and some fatâattached versions of a membrane protein, showing the method works but it doesnât change how the drug is used in people.
Abstract
Peptide ligation chemistry has revolutionized protein science by providing access to homogeneously modified peptides and proteins. However, lipidated polypeptides and integral membrane proteins-an important class of biomolecules-remain enormously challenging to access synthetically owing to poor aqueous solubility of one or more of the fragments under typical ligation conditions. Herein we describe the advent of a reductive diselenide-selenoester ligation (rDSL) method that enables efficient ligation of peptide fragments down to low nanomolar concentrations, without resorting to solubility tags or hybridizing templates. The power of rDSL is highlighted in the efficient synthesis of the FDA-approved therapeutic lipopeptide tesamorelin and palmitylated variants of the transmembrane lipoprotein phospholemman (FXYD1). Lipidation of FXYD1 was shown to critically modulate inhibitory activity against the Na<sup>+</sup>/K<sup>+</sup> pump.
Study Information
pubmed
2019
2019-12-31T00:00:00.000Z
10.1021/jacs.9b12558
49
56