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  • As also found by Stolarski et al inclusion of N

    2023-11-18

    As also found by Stolarski et al. [14], inclusion of N2O in the model is successful in reducing the effect of dynamics [13] in the lower stratosphere in the Northern Hemisphere (30–60°N in our case). The inclusion of N2O also decreased the error bars on the trend values, but the trend values still change substantially with altitude except in the upper stratosphere. The average upper stratospheric trend is −4.8 ± 0.2%/decade obtained by averaging the 3 values in the upper stratosphere from 1.5 hPa to 0.68 hPa; one standard deviation obtained by error propagation (i.e., square root of the sum of the squares of the original errors) is used as the error bar. Averaging the trend values over all 13 stratospheric pressure levels gives −5.0 ± 0.8%/decade, in which the error estimate is the standard deviation the trend values. Percentage trends were calculated by dividing the linear trends from the de-seasonalized time series by the mission average of the original time series.
    Acknowledgements The ACE mission is funded primarily by the Canadian Space Agency. We thank L. Froidevaux (Jet Propulsion Laboratory) for discussions on HCl trend values. We acknowledge NOAA Earth System Research Laboratory for providing the tropospheric chlorine data plotted in Fig. 1.
    Diabetes is a growing epidemic in both the developing and developed world. It has been estimated that there are ∼420 million diabetics globally with a projected global prevalence of 640 million in 2040. More than 70% of people suffering from Type 2 diabetes are hypertensive (blood pressure≥140/90mmHg). Additionally, studies have identified the risk of developing type 2 diabetes is much higher in people with 822 than in normotensives. An ideal treatment for this subset of diabetics would not only address their hyperglycemia but also the hypertensive component of the disease. DPP4 (dipeptidyl peptidase-4) inhibitors and ACE (angiotensin converting enzyme) inhibitors have been the mainstay for treating hyperglycaemia and hypertension in these patients. However, patient compliance becomes an issue when multiple drugs need to be taken on a long-term basis. In addition, there is the risk of enhanced drug-drug interactions when multiple drugs are prescribed. As a consequence, availability of a single therapeutic agent which would simultaneously ameliorate the pharmacological processes contributing to both hypertension and diabetes could be a significant step forward in the 822 treatment of metabolic syndrome. Here in, we report a designed multiple ligand approach to identify dual inhibitors which incorporate all the structural elements required for inhibition of DPP4 and ACE. One of the strategies for designing ligands capable of binding to two phylogenetically diverse biological targets is to merge the structural elements of two pharmacophores. Herein, the identification of molecular points on both ligands which would allow for merging of the two structures is the most critical step. Indeed, a detailed analysis of the pharmacophoric features, the size of the enzyme active sites and knowledge of the tolerability of the respective lead compounds to structural variations is an important exercise which aids in the design of dual merged ligands. In our work we critically evaluated ligand-DPP4 and ligand-ACE co-crystal structures, () to design dual inhibitors. Thus, ACE inhibitors (a) need a carboxy group to bind to the S2′ site, a zinc chelating group (COOH or SH), and a hydrophobic group that fits into the S1 pocket. ACE crystal structure further suggests that the S2′ pocket is big enough to accommodate large groups. From the structures of fosinoprilat () and zofenopril () (), it appears that position 4 of the proline ring in enalaprilat () is tolerant to further substitution without loss of activity and that these groups are well tolerated in S2′ pocket. DPP4 inhibitors, on the other hand, require a hydrophobic moiety (. trifluorophenyl) or an electrophilic group ( CN) to interact with a serine at the S1 site and a basic amine to form a salt bridge with the glutamic acid diad at the S2 site. A similar analysis of crystal structure of the DPP4 enzyme (b) suggests that the S2 pocket can accommodate large groups as in sitagliptin ( and similar compound (), (). Thus, based on the structural aspects of the ligands and enzymes, it appears that enalaprilat and sitagliptin can be merged to form a dual inhibitor by removing the relatively unessential triazolopiperidine of and forming an amide bond with an amino group placed at the fourth position of the proline residue of . Thus, the proposed dual inhibitor ligands – incorporate all the essential structural elements required for DPP4 and ACE inhibition ().