Thierry Brigaud

Poly(N-isopropylacrylamide) (PNIPAm)-based polymers are undoubtedly a promising solution for controlled drug delivery. This study presents the potential of such hydrogels in terms of stability for drug delivery property. Aging under thermal oxidative aging at 120°C for 2 months is performed and its consequences on drug delivery are investigated. First, two active pharmaceutical ingredients (API) (metronidazole, MTZ and orbifloxacin, ORBI) and PNIPAm-based polymers are fully characterized. Linear poly(N-isopropylacrylamide) demonstrates an immediate release of antibiotic-type active pharmaceutical ingredients (MTZ and ORBI) at 25°C and 37°C with over 90% API release after 1-hour period. For more complex systems, such as cross-linked networks and copolymers, controlled release of ORBI at 25°C and 37°C is achieved over a 24-hour period and only 80% API release with an initial burst release phase. Results showed a slight increase in glass transition after aging at 120°C for 2 months with a decrease in the macromolecular mobility of the polymer. Structural modifications induced by aging lead to variations in the release behavior of APIs. Over time, the release slows down, and the overall efficacy of the system diminishes drastically. 19F is used as a probe to monitor ORBI release by quantitative NMR spectrometry, and diffusion coefficients are determined by Diffusion Ordered SpectroscopY (DOSY) to characterize API-Hydrogels interactions. This work extends our understanding of the stability of poly(N-isopropylacrylamide)-based polymers, enabling a rational approach of their use as pharmaceutical excipients.

The trifluoromethylthio functional group (CF3S−) has gained considerable attention in synthetic and medicinal chemistry due to its ability to enhance the pharmacokinetic profiles of functionalized compounds. This Synopsis highlights recent progress in the incorporation of the CF3S group into biomolecules and bioactive compounds, with a focus on its influence on physicochemical properties and its applications in medicinal chemistry and chemical biology.

Peptide-based hydrogels are increasingly used in pharmaceutical and biomedical applications due to their versatility and biocompatibility. β-Hairpin design enhances β-strand alignment and fine-tunes hydrogel physicochemical properties. In this study, we investigate the design of β-hairpin hydrogelators from two P1-based (H-FQFQFK-NH₂) hexamer strands linked by a d-Pro-l-Pro β-turn. The fluorinated proline surrogate CF₃-ΨPro was evaluated for hairpin stabilization and gel properties. Hydrogels were characterized for physicochemical, mechanical, and structural properties, and selected hydrogels were screened in in vitro drug release experiments. Based on these data, in vivo hydrogel stability experiments were conducted on hairpin structures P3 (H-FQFQFKpPFQFQFK-NH₂) and its fluorinated analogue P17 (H-FQFQFKp(l-CF₃-ΨPro)FQFQFK-NH₂), via subcutaneous injection in mice. P3 and P17 demonstrated enhanced hydrogel lifespan with 70% and 45% of the hydrogel remaining at the injection site after 11 days, respectively, versus 10% for P1 after 7 days. These findings highlight the advantage of β-hairpin peptide hydrogels for prolonged drug delivery.

The incorporation of fluorinated amino acid residues into peptides represents a promising strategy for improving the pharmacokinetic properties of bioactive peptides. Herein, we report the solid-phase synthesis (SPPS) of a set of ten SCF₃- or CF₃-modified neuropeptide analogs based on endomorphin-1 (EM1). EM1, a selective subnanomolar μ-opioid receptor (μOR) agonist with poor metabolic stability (t_1/2 = 6 min in human plasma), was selected as a model to evaluate the effects of SCF₃ and CF₃ functionalization on the pharmacokinetic profile of short bioactive peptides. The syntheses of eight ready-to-use SCF₃- or CF₃-containing building blocks for SPPS and their incorporation into peptides are reported. In vitro μOR binding and functional activity assays demonstrated that most fluorinated analogs retained binding affinity and potency, accompanied by increased hydrophobicity. Among the series, modification of the pharmacophoric Tyr¹ residue with l-Dmt(3-SCF₃) yielded the most favorable profile (K_i = 1.4 nM, EC₅₀ = 0.9 nM). Plasma stability studies revealed a significant increase in half-life for this ligand (72-fold relative to EM1 and 14-fold relative to EM1(Dmt¹)), and thus, further demonstrated the potential of SCF₃-containing amino acids in therapeutic peptide design.

The development of chiral fluorinated biomolecules such as amino acids, peptides and pseudopeptides is attracting considerable interest at the frontiers of organic synthesis and biological chemistry. We propose in this review an overview of our contributions to organofluorine chemistry in connection with biological applications and also asymmetric synthesis these past twenty years in Université de Cergy-Pontoise (now CY Cergy Paris Université).

Peptide-based hydrogels are of interest to biomedical applications. Herein, we have explored the introduction of fluorinated amino acids in hydrogelator H-FQFQFK-NH₂ (P1) to design a series of fluorinated peptide hydrogels and evaluate the in vitro and in vivo properties of the most promising analogues. The impact of fluorinated groups on peptide gelation, secondary structure, and self-assembly processes was assessed. We show that fluorine can significantly improve hydrogel stiffness, compared to the nonfluorinated reference P1. For P15 (H-FQFQF(o-CF₃)K-NH₂), P18 (H-FQFQF(F₅)K-NH₂), and P19 (H-FQFQM(CF₃)K-NH₂), microscopy studies scrutinized fiber morphologies and alignment in the network. In vitro release studies of hydrogels loaded with an opioid cargo suggested improved hydrogel stability for P15 and P18. This improved stability was further validated in vivo, notably for P15, giving the most significant increased gel residence time, with more than 20% of hydrogel still present 9 days post-injection, as monitored by nuclear SPECT-CT imaging.

Introduction of CF₃-oxazolidines in polyproline type II foldamers maintains PPII helicity, non-cytotoxicity and stability towards proteolysis. The CF₃ groups enhanced hydrophobicity and are used as easy-to-handle ¹⁹F NMR probes.

Oligomers of the achiral α‐aminoisobutyric acid (Aib) adopt a 3₁₀ helical conformation in which the screw‐sense preference can be controlled by a single chiral residue. The use of the fluorinated residue α‐Trifluoromethylalanine (α‐TfmAla) revealed a unique way to both induce and measure the screw‐sense preference of such oligomers acting as ¹⁹F NMR probe. This work proposes a systematic study of the effect of this fluorinated chiral inducer on the helical screw‐sense preference of poly‐Aib oligomers. The impact of the position of the fluorinated residue into pentamers (N‐terminal, central or C‐terminal) as well as the nature of the C‐terminal capping of the peptides was thoroughly studied in light of complete structural analysis. A deeper understanding of the fluorine effect was achieved confirming the unique ability of α‐TfmAla as a helical screw‐sense controller.

Due to the specific properties provided by fluorine atoms to biomolecules, amino acids with fluorinated side chains are of great interest for medicinal chemistry and chemical biology. Among them, α-fluoroalkyl-α-amino acids constitute a unique class of compounds. In this review, we outline the strategies adopted for their syntheses in enantiopure or enantioenriched forms and their incorporation into peptides. We then describe the consequences of the introduction of fluorine atoms in these compounds for the modulation of their hydrophobicity and the control of their conformation. Emerging applications are presented in the areas of enzyme inhibition, medicinal chemistry, hydrolytic stability of peptides, antimicrobial peptides, PET, and ¹⁹F NMR probes.

The straightforward synthesis of chiral (R)- and (S)-difluoroalanine is reported. The key step is a Strecker-type reaction followed by hydrogenolysis, Fmoc protection, and acidic hydrolysis. Peptide coupling reactions at its N- and C-terminal positions provide diastereomerically pure tripeptides. On the basis of hydrophobicity index measurements, the hydrophobic contribution of difluoroalanine in a peptide chain was found to be similar to that of isoleucine for a smaller van der Waals volume of the side chain.