Article
Chemistry, Medicinal
Tobias Grabe, Kirujan Jeyakumar, Janina Niggenaber, Tom Schulz, Sandra Koska, Silke Kleinboelting, Michael Edmund Beck, Matthias P. Mueller, Daniel Rauh
Summary: Reversible EGFR inhibitors based on the methylindole-aminopyrimidine scaffold and the affinity driving isopropyl ester of mobocertinib have been developed to overcome EGFR-C797S resistance mutation. These inhibitors showed subnanomolar activity against EGFR-L858R/C797S and EGFR-L858R/T790M/C797S, and exhibited cellular activity on EGFR-L858R/C797S dependent Ba/F3 cells. The cocrystal structures of these inhibitors provide guidance for further inhibitor design targeting C797S-mutated EGFR.
ACS MEDICINAL CHEMISTRY LETTERS
(2023)
Article
Engineering, Environmental
Chuansheng Wang, Meiyue Ding, Tze Chiang Albert Ng, How Yong Ng
Summary: Vibrating membrane (VM) technology has been successfully applied in the vibrating AnMBR (V-AnMBR) for long-term municipal wastewater treatment, showing superior performance in terms of longer filtration time, increased organics removal, and higher methane yields compared to the conventional biogas-scouring AnMBR (C-AnMBR). The study also revealed that VM reduced the fouling layer and minimized biomass breakdowns and fouling contributors, providing in-depth explanations of fouling development and mechanisms of VM for sustainable AnMBR technology.
CHEMICAL ENGINEERING JOURNAL
(2023)
Article
Biophysics
Amy Lam, Orville O. Kirkland, Papa Freduah Anderson, Nandini Seetharaman, Dragan Vujovic, Patricia A. Thibault, Kristopher D. Azarm, Benhur Lee, Robert J. Rawle
Summary: In this study, we used fluorescence microscopy to observe the binding process of Sendai virus to supported lipid bilayers at the single-particle level and investigated the mechanisms of this binding. We found that the binding of Sendai virus is dependent on the chemical structural features of the receptor and the density of the receptor. After binding, the virus exhibits a rolling motion. Furthermore, we studied the relationship between binding and target cholesterol concentration.
BIOPHYSICAL JOURNAL
(2022)
Article
Oncology
Tong-Hong Wang, Chih-Ching Wu, Kuo-Yen Huang, Yann-Lii Leu, Shuenn-Chen Yang, Ci-Ling Chen, Chi-Yuan Chen
Summary: This study utilized CRISPR/Cas9 technology to introduce the EGFR C797S mutation into an NSCLC cell line, revealing an association between differentially expressed genes/proteins and increased AXL expression in cells with the mutation. Inhibition of AXL showed effectiveness in slowing the growth of NSCLC cells carrying EGFR C797S, suggesting it could be a potential treatment strategy for this type of TKI resistance.
Review
Public, Environmental & Occupational Health
Natnael Atnafu Gebeyehu, Kirubel Dagnaw Tegegne, Gebyaw Biset, Dagne Addisu Sewuyew, Biresaw Wassihun Alemu, Alemker Mola Yitayew
Summary: In Ethiopia, the pooled prevalence of discontinuation of long-acting contraceptives is high, with factors such as side effects, lack of counseling on side effects, and dissatisfaction with provided services contributing to this phenomenon. Healthcare professionals should focus on the client's reproductive goals, proper management of side effects, counseling, and post-insertion visits to address this public health issue effectively.
FRONTIERS IN PUBLIC HEALTH
(2022)
Article
Immunology
Nkuchia M. M'ikanatha, Xin Yin, Sameh W. Boktor, Lisa A. Dettinger, Deepanker Tewari
Summary: The integrated surveillance conducted in Pennsylvania revealed a significant proportion of multidrug-resistant NTS isolates from both human and animal sources, with 16% having genetic mechanisms that confer resistance to ceftriaxone.
OPEN FORUM INFECTIOUS DISEASES
(2021)
Article
Chemistry, Medicinal
Alessandro Papa, Silvia Pasquini, Francesca Galvani, Mariarosaria Cammarota, Chiara Contri, Gabriele Carullo, Sandra Gemma, Anna Ramunno, Stefania Lamponi, Beatrice Gorelli, Simona Saponara, Katia Varani, Marco Mor, Giuseppe Campiani, Francesca Boscia, Fabrizio Vincenzi, Alessio Lodola, Stefania Butini
Summary: The neuroprotective performance of the endocannabinoid system (ECS) against neuroinflammation can be significantly enhanced by inhibiting the key ECS enzyme FAAH. In this study, a series of carbamate-based FAAH inhibitors were developed with improved drug properties compared to previous analogues. These inhibitors showed nanomolar potency, good water solubility, and chemical stability. They exhibited excellent selectivity against monoacylglycerol lipase and cannabinoid receptors, and demonstrated reversible mechanisms of action without toxicity or cardiac effects. Selected analogues displayed notable neuroprotective effects against oxidative stress and neuroinflammation.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Santiago Movilla, Sergio Marti, Maite Roca, Vicent Moliner
Summary: Alzheimer???s disease is a major challenge in biomedical sciences due to its increasing prevalence and lack of effective treatments. A recent study focuses on the cysteine protease RgpB as a promising drug target, using computational methods to study potential inhibitors. Molecular dynamics simulations and quantum mechanics/molecular mechanics (QM/MM) molecular dynamics (MD) simulations were performed to understand the inhibitory mechanism. The results provide insights for the future design of Alzheimer???s disease inhibitors.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Article
Pharmacology & Pharmacy
Francesca Romana Ferrari, Carmine Giorgio, Alfonso Zappia, Vigilio Ballabeni, Simona Bertoni, Elisabetta Barocelli, Laura Scalvini, Francesca Galvani, Marco Mor, Alessio Lodola, Massimiliano Tognolini
Summary: It has been demonstrated that the Eph-ephrin system, particularly the EphA2 receptor, plays a key role in supporting tumor growth, invasion, metastasis, and neovascularization. In this study, new commercially available FXR agonists, including Cilofexor, Nidufexor, Tropifexor, Turofexorate isopropyl, and Vonafexor, were characterized as potential Eph ligands. Molecular modeling investigations and binding assays showed that Cilofexor specifically and reversibly binds to the EphA2 receptor with a ki value in the low micromolar range.
BIOCHEMICAL PHARMACOLOGY
(2023)
Article
Chemistry, Medicinal
Francesca Galvani, Daniele Pala, Alberto Cuzzolin, Laura Scalvini, Alessio Lodola, Marco Mor, Andrea Rizzi
Summary: In this study, two metadynamics protocols were used to estimate the residence times of muscarinic M3 receptor antagonists. The results showed that both computational methods were able to accurately rank compounds according to their experimental residence times.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Article
Chemistry, Multidisciplinary
Santiago Movilla, Maite Roca, Vicent Moliner, Alessandra Magistrato
Summary: The spliceosome machinery catalyzes pre-mRNA splicing with the help of RNA-dependent ATPases/helicases. The ATPase function of Prp2 is activated by RNA binding, which triggers specific interactions and optimally positions the nucleophilic water and general base for ATP hydrolysis. This mechanism is conserved in DExH-box helicases and may be applicable to the entire family.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2023)
Article
Multidisciplinary Sciences
Katarzyna Swiderek, Susana Velasco-Lozano, Miquel A. Galmes, Ion Olazabal, Haritz Sardon, Fernando Lopez-Gallego, Vicent Moliner
Summary: Biocatalysis plays a crucial role in plastic recycling. However, the understanding of the molecular mechanisms governing the catalytic performance of plastic-degrading enzymes is limited, hindering the development of more efficient enzyme-based technologies. This study investigates the hydrolysis of PET-derived diesters and PET trimers using CALB and provides insights into CALB's regioselectivity. The findings enable selective hydrolysis of BHET and offer potential applications in the valorization of PET by-products.
NATURE COMMUNICATIONS
(2023)
Article
Chemistry, Physical
Kemel Arafet, Santiago Royo, Tanja Schirmeister, Fabian Barthels, Florenci V. Gonzalez, Vicent Moliner
Summary: This study presents a research on proposed covalent inhibitors of cysteine proteases (CPs) cruzain and cathepsin L, using design, synthesis, kinetic measurements, and QM/MM computational simulations on dipeptidyl nitroalkene compounds. The experimental inhibition data and predicted inhibition constants derived from the free energy landscape of the full inhibition process provide insights into the impact of the recognition part and modifications on the P2 site. The designed compounds, especially the one with a bulky group (Trp) at the P2 site, show promising in vitro inhibition activities against cruzain and cathepsin L, holding potential for drug development and future designs for the treatment of human diseases.
Article
Chemistry, Medicinal
Lorenzo Guidetti, Alfonso Zappia, Laura Scalvini, Francesca Romana Ferrari, Carmine Giorgio, Riccardo Castelli, Francesca Galvani, Federica Vacondio, Silvia Rivara, Marco Mor, Chiara Urbinati, Marco Rusnati, Massimiliano Tognolini, Alessio Lodola
Summary: In this study, a combined experimental and computational approach was used to investigate the molecular basis of the recognition between a prototypical Eph-ephrin antagonist and two representative receptors of the EphA and EphB subfamilies. The findings led to the design and synthesis of a novel antagonist selective for the EphA2 receptor.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Article
Chemistry, Physical
Adrian Fernandez-de-la-Pradilla, Santiago Royo, Tanja Schirmeister, Fabian Barthels, Katarzyna Swiderek, Florenci V. Gonzalez, Vicent Moliner
Summary: This study focuses on the design and characterization of potential inhibitors of Cathepsin L (CatL) and their inhibitory mechanism. The results demonstrate the effectiveness of the designed compounds in inhibiting CatL and highlight the importance of the structural features of the compounds in enzyme inhibition. The findings provide valuable insights for the design of inhibitors and the development of drugs for cancer treatment.
Article
Chemistry, Medicinal
Claudio Festuccia, Miriam Corrado, Alessandra Rossetti, Riccardo Castelli, Alessio Lodola, Giovanni Luca Gravina, Massimiliano Tognolini, Carmine Giorgio
Summary: This study demonstrated the inhibitory effects of Eph antagonism on prostate cancer both in vitro and in vivo. The Eph antagonist UniPR1331 inhibited PC3 cell growth, induced apoptosis, and downregulated epithelial mesenchymal transition markers. Furthermore, UniPR1331 reduced PC3 cell migration, invasion, and vasculomimicry capabilities.
