New insights into structure and function of bis-phosphinic acid derivatives and implications for CFTR modulation.

C407 is a compound that corrects the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein carrying the p.Phe508del (F508del) mutation. We investigated the corrector effect of c407 and its derivatives on F508del-CFTR protein. Molecular docking and dynamics simulations combined with site-directed mutagenesis suggested that c407 stabilizes the F508del-Nucleotide Binding Domain 1 (NBD1) during the co-translational folding process by occupying the position of the p.Phe1068 side chain located at the fourth intracellular loop (ICL4). After CFTR domains assembly, c407 occupies the position of the missing p.Phe508 side chain. C407 alone or in combination with the F508del-CFTR corrector VX-809, increased CFTR activity in cell lines but not in primary respiratory cells carrying the F508del mutation. A structure-based approach resulted in the synthesis of an extended c407 analog G1, designed to improve the interaction with ICL4. G1 significantly increased CFTR activity and response to VX-809 in primary nasal cells of F508del homozygous patients. Our data demonstrate that in-silico optimized c407 derivative G1 acts by a mechanism different from the reference VX-809 corrector and provide insights into its possible molecular mode of action. These results pave the way for novel strategies aiming to optimize the flawed ICL4-NBD1 interface.

Modulators of CFTR. Updates on clinical development and future directions.

Cystic fibrosis (CF) is the most frequent life-limiting autosomal recessive disorder in the Caucasian population. It is due to mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. Current symptomatic CF therapies, which treat the downstream consequences of CFTR mutations, have increased survival. Better knowledge of the CFTR protein has enabled pharmacologic therapy aiming to restore mutated CFTR expression and function. These CFTR "modulators" have revolutionised the CF therapeutic landscape, with the potential to transform prognosis for a considerable number of patients. This review provides a brief summary of their mechanism of action and presents a thorough review of the results obtained from clinical trials of CFTR modulators.

Highly Porous Hybrid Metal-Organic Nanoparticles Loaded with Gemcitabine Monophosphate: a Multimodal Approach to Improve Chemo- and Radiotherapy.

Nanomedicine recently emerged as a novel strategy to improve the performance of radiotherapy. Herein we report the first application of radioenhancers made of nanoscale metal-organic frameworks (nanoMOFs), loaded with gemcitabine monophosphate (Gem-MP), a radiosensitizing anticancer drug. Iron trimesate nanoMOFs possess a regular porous structure with oxocentered Fe trimers separated by around 5 Š(trimesate linkers). This porosity is favorable to diffuse the electrons emitted from nanoMOFs due to activation by γ radiation, leading to water radiolysis and generation of hydroxyl radicals which create nanoscale damages in cancer cells. Moreover, nanoMOFs act as "Trojan horses", carrying their Gem-MP cargo inside cancer cells to interfere with DNA repair. By displaying different mechanisms of action, both nanoMOFs and incorporated Gem-MP contribute to improve radiation efficacy. The radiation enhancement factor of Gem-MP loaded nanoMOFs reaches 1.8, one of the highest values ever reported. These results pave the way toward the design of engineered nanoparticles in which each component plays a role in cancer treatment by radiotherapy.

Metallic bismuth nanoparticles: Towards a robust, productive and ultrasound assisted synthesis from batch to flow-continuous chemistry.

Bismuth is a highly biocompatible and inexpensive metal with a high atomic number, which confers an important X-rays opacity. While bismuth oxide or bismuth sulphide have been extensively studied in imaging, little is known about metallic bismuth nanoparticles. The latter are more attractive for X-rays imaging because they contain neither oxygen nor sulfur, so that a high amount of metal atoms is contained within the nanoparticles. We report here a robust, efficient and green ultrasound assisted synthesis to obtain metallic bismuth NPs. The procedure, which has been optimized to get a reproducible synthesis, will also tend to minimize chemical hazards to health and environment. By applying the green chemistry principles, several experimental parameters have been studied such as reaction time, reactants stoichiometry, temperature, starting material quantities and purification steps number. Two energy delivery system (classical heating and sonication) were compared. The production of small metallic bismuth NPs on a large scale by flow chemistry coupled to sonication was showed for the first time. These optimizations of the process were completed by a comparison of two purification methods (centrifugation and ultrafiltration) to isolate purified thin black powders of d-glucose-coated bismuth NPs. Several analytical techniques were used to characterize products (structures, sizes and morphology) such as Fourier Transform InfraRed (FT-IR) spectroscopy, Dynamic Light Scattering (DLS), Transmission Electron Microscopy (TEM), Energy-dispersive X-ray spectrometry (EDX) and X-Ray Diffraction (XRD). All these analyses corroborated well with the structure of metallic bismuth NPs coated with a d-glucose shell.

A novel codrug made of the combination of ethionamide and its potentiating booster: synthesis, self-assembly into nanoparticles and antimycobacterial evaluation.

Ethionamide (ETH) is one of the most widely used second-line chemotherapeutic drugs for the treatment of multi-drug-resistant tuberculosis. The bioactivation and activity of ETH is dramatically potentiated by a family of molecules called "boosters" among which BDM43266 is one of the most potent. However, the co-administration of these active molecules is hampered by their low solubility in biological media and by the strong tendency of ETH to crystallize. A novel strategy that involves synthesizing a codrug able to self-associate into nanoparticles prone to be taken up by infected macrophages is proposed here. This codrug is designed by tethering N-hydroxymethyl derivatives of both ETH and its booster through a glutaric linker. This codrug self-assembles into nanoparticles of around 200 nm, stable upon extreme dilution without disaggregating as well as upon concentration. The nanoparticles of the codrug can be intranasally administered overcoming the unfavorable physico-chemical profiles of the parent drugs. Intrapulmonary delivery of the codrug nanoparticles to Mtb infected mice via the intranasal route at days 7, 9, 11, 14, 16 and 18 post-infection reduces the bacterial load in the lungs by a factor of 6.

Nanoparticles with high payloads of pipemidic acid, a poorly soluble crystalline drug: drug-initiated polymerization and self-assembly approach.

Nowadays, biodegradable polymers such as poly(lactic acid) (PLA), poly(D,L-lactic-co-glycolic acid) (PLGA) and poly(ε-caprolactone) (PCL) remain the most common biomaterials to produce drug-loaded nanoparticles (NPs). Pipemidic acid (PIP) is a poorly soluble antibiotic with a strong tendency to crystallize. PIP incorporation in PLA/PLGA NPs was challenging because of PIP crystals formation and burst release. As PIP had a poor affinity for the NPs, an alternative approach to encapsulation was used, consisting in coupling PIP to PCL. Thus, a PCL-PIP conjugate was successfully synthesized by an original drug-initiated polymerization in a single step without the need of catalyst. PCL-PIP was characterized by NMR, IR, SEC and mass spectrometry. PCL-PIP was used to prepare self-assembled NPs with PIP contents as high as 27% (w/w). The NPs were characterized by microscopy, DLS, NTA and TRPS. This study paves the way towards the production of NPs with high antibiotic payloads by drug-initiated polymerization. Further studies will deal with the synthesis of novel polymer-PIP conjugates with ester bonds between the drug and PCL. PIP can be considered as a model drug and the strategy developed here could be extended to other challenging antibiotics or anticancer drugs and employed to efficiently incorporate them in NPs.

High-throughput production of two disulphide-bridge toxins.

A quick and efficient production method compatible with high-throughput screening was developed using 36 toxins belonging to four different families of two disulphide-bridge toxins. Final toxins were characterized using HPLC co-elution, CD and pharmacological studies.