Publications by authors named "O Pasquier"
Background: The therapeutic potential of relaxin for heart failure and renal disease in clinical trials is hampered by the short half-life of serelaxin. Optimization of fatty acid-acetylated single-chain peptide analogues of relaxin culminated in the design and synthesis of R2R01, a potent and selective RXFP1 agonist with subcutaneous bioavailability and extended half-life.
Experimental Approach: Cellular assays and pharmacological models of RXFP1 activation were used to validate the potency and selectivity of R2R01.
We recently described C18 fatty acid acylated peptides as a new class of potent long-lasting single-chain RXFP1 agonists that displayed relaxin-like activities in vivo. Early pharmacokinetics and toxicological studies of these stearic acid acylated peptides revealed a relevant oxidative metabolism occurring in dog and minipig, and also seen at a lower extent in monkey and rat. Mass spectrometry combined to NMR spectroscopy studies revealed that the oxidation occurred, unexpectedly, on the stearic acid chain at ω-1, ω-2 and ω-3 positions.
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- Researchers developed a new peptide called SA10SC-RLX that has a longer half-life and can be administered subcutaneously, overcoming the limitations of recombinant relaxin-2 that requires intravenous use.
- SA10SC-RLX has high activity on human RXFP1, showing positive renal effects in rats, such as increased kidney blood flow and reduced resistance, similar to relaxin's effects in humans.
- This new peptide represents a promising option for treating chronic fibrotic and cardiovascular diseases, as it allows for once-daily subcutaneous administration, making it more practical for patients.
Article Synopsis
- Human relaxin-2 is a hormone important for mediating blood flow changes during pregnancy and has potential benefits in treating acute heart failure, but its clinical use is limited due to a short half-life and requirement for intravenous administration.
- Researchers developed long-acting relaxin peptide mimetics by modifying the B-chain of relaxin, leading to simpler and more potent peptide agonists for the relaxin receptor RXFP1.
- These new lipidated peptide agonists demonstrated high activity, better bioavailability when taken subcutaneously, and longer half-lives, making them promising candidates for wider therapeutic use.
The neonatal Fc receptor (FcRn) promotes antibody recycling through rescue from normal lysosomal degradation. The binding interaction is pH-dependent with high affinity at low pH, but not under physiological pH conditions. Here, we combined rational design and saturation mutagenesis to generate novel antibody variants with prolonged half-life and acceptable development profiles.
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