Rescue of Mutant CFTR Channel Activity by Investigational Co-Potentiator Therapy Mafalda Bacalhau, Filipa C. Ferreira, Marcelo Folhadella M. F. Azevedo, Talita P. Rosa, Camilla D. Buarque, et al. Biomedicines, 2025 Background: The potentiator VX-770 (ivacaftor) has been approved as a monotherapy for over 95 cystic fibrosis (CF)-causing variants associated with gating/conductance defects of the CF transmembrane conductance regulator (CFTR) channel. However, despite its therapeutic success, VX-770 only partially restores CFTR activity for many of these variants, indicating they may benefit from the combination of potentiators exhibiting distinct mechanisms of action (i.e., co-potentiators). We previously identified LSO-24, a hydroxy-1,2,3-triazole-based compound, as a modest potentiator of p.Arg334Trp-CFTR, a variant with a conductance defect for which no modulator therapy is currently approved. Objective/Methods: We synthesized a new set of LSO-24 structure-based compounds, screened their effects on p.Arg334Trp-CFTR activity, and assessed the additivity of hit compounds to VX-770, ABBV-974, ABBV-3067, and apigenin. After validation by electrophysiological assays, the most promising hits were also assessed in cells expressing other variants with defective gating/conductance, namely p.Pro205Ser, p.Ser549Arg, p.Gly551Asp, p.Ser945Leu, and p.Gly1349Asp. Results: We found that five compounds were able to increase p.Arg334Trp-CFTR activity with similar efficacy, but slightly greater potency promoted by LSO-150 and LSO-153 (EC50: 1.01 and 1.26 μM, respectively). These two compounds also displayed a higher rescue of p.Arg334Trp-CFTR activity in combination with VX-770, ABBV-974, and ABBV-3067, but not with apigenin. When tested in cells expressing other CFTR variants, LSO-24 and its derivative LSO-150 increased CFTR activity for the variants p.Ser549Arg, p.Gly551Asp, and p.Ser945Leu with a further effect in combination with VX-770 or ABBV-3067. No potentiator was able to rescue CFTR activity in p.Pro205Ser-expressing cells, while p.Gly1349Asp-CFTR responded to VX-770 and ABBV-3067 but not to LSO-24 or LSO-150. Conclusions: Our data suggest that these new potentiators might share a common mechanism with apigenin, which is conceivably distinct from that of VX-770 and ABBV-3067. The additive rescue of p.Arg334Trp-, p.Ser549Arg-, p.Gly551Asp-, and p.Ser945Leu-CFTR also indicates that these variants could benefit from the development of a co-potentiator therapy.
Covalent Organic Frameworks as a Versatile Platform for Iron-Catalyzed sp3 C−H Activation and Cross-Coupling via Decarboxylative Oxidation Jhonny M. C. Cifuentes, Fábio J. F. S. Henrique, Carolina B. P. Ligiéro, Pierre M. Esteves, Camilla D. Buarque European Journal of Inorganic Chemistry, 2024 This work demonstrates the oxidative cross‐coupling of cinnamic acids with toluene using FeCl3 immobilized on a covalent organic framework (COF) pore wall, resulting in the synthesis of 1,3‐arylpropene derivatives. This iron‐based heterogeneous catalytic system affords the desired products in moderate yields ranging from 51 % to 65 %. Investigations using COFs with varying pore sizes indicate that larger pores facilitate the reaction, suggesting a spatial requirement for this transformation within the catalyst. The correlation between pore size and reaction efficiency provides insights into developing tailored catalysts to match the spatial requirements of the transformation. This version emphasizes the novelty of the study and the synthesis of 1,3‐arylpropene derivatives. It also clarifies that the iron‐based heterogeneous catalytic system is responsible for the reaction. Additionally, it provides a more detailed explanation of the findings regarding pore size and spatial requirements.
Organic Synthesis and Current Understanding of the Mechanisms of CFTR Modulator Drugs Ivacaftor, Tezacaftor, and Elexacaftor Filipa Ferreira, Camilla Buarque, Miquéias Lopes-Pacheco Molecules, 2024 The monogenic rare disease Cystic Fibrosis (CF) is caused by mutations in the gene encoding the CF transmembrane conductance (CFTR) protein, an anion channel expressed at the apical plasma membrane of epithelial cells. The discovery and subsequent development of CFTR modulators—small molecules acting on the basic molecular defect in CF—have revolutionized the standard of care for people with CF (PwCF), thus drastically improving their clinical features, prognosis, and quality of life. Currently, four of these drugs are approved for clinical use: potentiator ivacaftor (VX-770) alone or in combination with correctors lumacaftor, (VX-809), tezacaftor (VX-661), and elexacaftor (VX-445). Noteworthily, the triple combinatorial therapy composed of ivacaftor, tezacaftor, and elexacaftor constitutes the most effective modulator therapy nowadays for the majority of PwCF. In this review, we exploit the organic synthesis of ivacaftor, tezacaftor, and elexacaftor by providing a retrosynthetic drug analysis for these CFTR modulators. Furthermore, we describe the current understanding of the mechanisms of action (MoA’s) of these compounds by discussing several studies that report the key findings on the molecular mechanisms underlying their action on the CFTR protein.
Antiviral evaluation of 1,4-disubstituted-1,2,3-triazole derivatives against Chikungunya virus Vitor Won-Held Rabelo, Verônica Diniz da Silva, Maria Leonisa Sanchez Nuñez, Leonardo dos Santos Corrêa Amorim, Camilla Djenne Buarque, et al. Future Virology, 2023 Aim: This work aimed to investigate the antiviral activity of two 1,4-disubstituted-1,2,3-triazole derivatives (1 and 2) against Chikungunya virus (CHIKV) replication. Materials & methods: Cytotoxicity was analyzed using colorimetric assays and the antiviral potential was evaluated using plaque assays and computational tools. Results: Compound 2 showed antiviral activity against CHIKV 181-25 in BHK-21 and Vero cells. Also, this compound presented a higher activity against CHIKV BRA/RJ/18 in Vero cells, like compound 1. Compound 2 exhibited virucidal activity and inhibited virus entry while compound 1 inhibited virus release. Molecular docking suggested that these derivatives inhibit nsP1 protein while compound 1 may also target capsid protein. Conclusion: Both compounds exhibit promising antiviral activity against CHIKV by blocking different steps of virus replication.
Synthesis, characterization and crystal structure of methyl 2-(2-oxo-2H-chromen-4-ylamino)benzoate Henrique V. P. Hollauer, Rachel C. Vilas Novas, Guilherme P. Guedes, Camilla D. Buarque, Lívia B. L. Escobar Acta Crystallographica Section E Crystallographic Communications, 2023 Methyl 2-(2-oxo-2H-chromen-4-ylamino)benzoate, C17H13NO4 (1), was prepared by condensation between 4-hydroxycoumarin and methyl 2-aminobenzoate. It crystallizes in the orthorhombic space group Pca21 at 300 K. The molecule of compound 1 consists of the 2H-chromen-2-one part connected by an amine moiety (–NH–) to the methyl benzoate ring. The supramolecular array is formed by hydrogen bonds between the aromatic ring and the O atoms of the lactone and ester portions. The structural details match the spectroscopic data acquired from NMR and IR spectroscopy.
