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Inhibition of CDK2/CA (cyclin-dependent kinase 2/cyclin A complex) activity through blocking of the substrate recognition site in the cyclin A subunit has been demonstrated to be an effective method for inducing apoptosis in tumor cells. We have used the cyclin binding motif (CBM) present in the tumor suppressor proteins p21(WAF1) and p27(KIP1) as a template to optimize the minimal sequence necessary for CDK2/CA inhibition. A series of peptides were prepared, containing nonnatural amino acids, which possess nano- to micromolar CDK2-inhibitory activity. Here we present X-ray structures of the protein complex CDK2/CA, together with the cyclin groove-bound peptides H-Ala-Ala-Abu-Arg-Ser-Leu-Ile-(p-F-Phe)-NH(2) (peptide 1), H-Arg-Arg-Leu-Ile-Phe-NH(2) (peptide 2), Ac-Arg-Arg-Leu-Asn-(m-Cl-Phe)-NH(2) (peptide 3), H-Arg-Arg-Leu-Asn-(p-F-Phe)-NH(2) (peptide 4), and H-Cit-Cit-Leu-Ile-(p-F-Phe)-NH(2) (peptide 5). Some of the peptide complexes presented here were obtained through the novel technique of ligand exchange within protein crystals. This method may find general application for obtaining complex structures of proteins with surface-bound ligands.

Abstract. Poor air quality is currently responsible for large impacts on human health across the world. In addition, the air pollutants, ozone (O3) and particulate matter less than 2.5 microns in diameter (PM2.5), are also radiatively active in the atmosphere and can influence Earth’s climate. It is important to understand the effect of air quality and climate mitigation measures over the historical period and in different future scenarios to ascertain any impacts from air pollutants on both climate and human health. The 6th Coupled Model Intercomparison Project (CMIP6) presents an opportunity to analyse the change in air pollutants simulated by the current generation of climate and Earth system models that include a representation of chemistry and aerosols (particulate matter). The shared socio-economic pathways (SSPs) used within CMIP6 encompass a wide range of trajectories in precursor emissions and climate change, allowing for an improved analysis of future changes to air pollutants. Firstly, we conduct an evaluation of the available CMIP6 models against surface observations of O3 and PM2.5. CMIP6 models show a consistent overestimation of observed surface O3 concentrations across most regions and in most seasons, with a large diversity in simulated values over northern hemisphere continental regions. Conversely, observed surface PM2.5 concentrations are consistently underestimated by CMIP6 models, particularly for the northern hemisphere winter months, with the largest model diversity near natural emission source regions. Over the historical period (1850–2014) large increases in both surface O3 and PM2.5 are simulated by the CMIP6 models across all regions, particularly over the mid to late 20th Century when anthropogenic emissions increase markedly. Large regional historical changes are simulated for both pollutants, across East and South Asia, with an increase of up to 40 ppb for O3 and 12 µg m-3 for PM2.5. In future scenarios containing strong air quality and climate mitigation measures (ssp126), air pollutants are substantially reduced across all regions by up to 15 ppb for O3 and 12 µg m-3 for PM2.5. However, for scenarios that encompass weak action on mitigating climate and reducing air pollutant emissions (ssp370), increases of both surface O3 (up 10 ppb) and PM2.5 (up to 8 µg m-3) are simulated across most regions. Although, for regions like North America and Europe small reductions in PM2.5 are simulated in this scenario. A comparison of simulated regional changes in both surface O3 and PM2.5 from individual CMIP6 models highlights important differences due to the interaction of aerosols, chemistry, climate and natural emission sources within models. The prediction of regional air pollutant concentrations from the latest climate and Earth system models used within CMIP6 shows that the particular future trajectory of climate and air quality mitigation measures could have important consequences for regional air quality, human health and near-term climate. Differences between individual models emphasises the importance of understanding how future Earth system feedbacks influence natural emission sources.

Cystic fibrosis (CF) is caused by mutations in the gene for the cystic fibrosis transmembrane conductance regulator (CFTR). With the discovery of Ivacaftor and Orkambi, it has been shown that CFTR function can be partially restored by administering one or more small molecules. These molecules aim at either enhancing the amount of CFTR on the cell surface (correctors) or at improving the gating function of the CFTR channel (potentiators). Here we describe the discovery of a novel potentiator GLPG1837, which shows enhanced efficacy on CFTR mutants harboring class III mutations compared to Ivacaftor, the first marketed potentiator. The optimization of potency, efficacy, and pharmacokinetic profile will be described.