Synthesis and Biological Evaluation of Pyrazole-Pyrimidones as a New Class of Correctors of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR).

Cystic fibrosis (CF) is caused by the functional expression defect of the cystic fibrosis transmembrane conductance regulator (CFTR) protein. Despite the recent success in CFTR modulator development, the available correctors only partially restore the F508del-CFTR channel function, and several rare CF mutations show resistance to available drugs. We previously identified compound that synergistically rescued the F508del-CFTR folding defect in combination with the existing corrector drugs VX-809 and VX-661.

Assessing the interaction between hemoglobin and the receptor binding domain of SARS-CoV-2 spike protein through MARTINI coarse-grained molecular dynamics.

The emergence of different coronavirus-related diseases in the 2000's (SARS, MERS, and Covid-19) warrants the need of a complete understanding of the pathological, biological, and biochemical behavior of this class of pathogens. Great attention has been paid to the SARS-CoV-2 Spike protein, and its interaction with the human ACE2 has been thoroughly investigated. Recent findings suggested that the SARS-CoV-2 components may interact with different human proteins, and hemoglobin has very recently been demonstrated as a potential target for the Spike protein.

Influence of Timing of Maternal Pertussis Immunization on the Avidity of Transferred Antibodies in Term and Preterm Neonates.

The timing of maternal pertussis vaccination influences the titers of cord-blood anti-pertussis antibodies. Whether it affects their avidity is unknown. We demonstrate in 298 term and 72 preterm neonates that antibody avidity is independent of the timing of maternal vaccination, whether comparing second with third trimester or intervals before birth.

New TMA (4,6,4'-Trimethyl angelicin) Analogues as Anti-Inflammatory Agents in the Treatment of Cystic Fibrosis Lung Disease.

A series of new-generation TMA (4,6,4'-trimethyl angelicin) analogues was projected and synthetized in order to ameliorate anti-inflammatory activity, with reduced or absent toxicity. Since the NF-κB transcription factor (TF) plays a critical role in the expression of IL-8 (Interluekin 8), a typical marker of lung inflammation in Cystic Fibrosis (CF), the use of agents able to interfere with the NF-κB pathway represents an interesting therapeutic strategy. Through preliminary EMSA experiments, we identified several new TMA derivatives able to inhibit the NF-κB/DNA complex.

Improved Trimethylangelicin Analogs for Cystic Fibrosis: Design, Synthesis and Preliminary Screening.

A small library of new angelicin derivatives was designed and synthesized with the aim of bypassing the side effects of trimethylangelicin (TMA), a promising agent for the treatment of cystic fibrosis. To prevent photoreactions with DNA, hindered substituents were inserted at the 4 and/or 6 positions. Unlike the parent TMA, none of the new derivatives exhibited significant cytotoxicity or mutagenic effects.