Molecular design and systematic optimization of a halogen-bonding system between the asthma interleukin-5 receptor and its cyclic peptide ligand.

Human interleukin-5 (IL-5) functions as an important pro-inflammatory factor by binding to its specific receptor, IL-5Rα, which has been implicated in the pathogenesis of asthma. Previously, a disulfide-bonded cyclic peptide AF17121 obtained from random library screening and sequence variation was found to competitively disrupt the cognate IL-5Rα/IL-5 interaction with moderate potency. In this study, the crystal complex of IL-5Rα with AF17121 was investigated at structural and energetic levels. It is revealed that the side-chain indole moiety of the AF17121 Trp5 residue is a potential site for a stem putative halogen bond (X-bond) with IL-5Rα, which is just located within the key 3 EXXR6 motif region recognized specifically by IL-5Rα. We systematically examined four halogen substitution types at five positions of the indole moiety; QM/MM calculations theoretically unraveled that only halogenations at 5 and 6 positions can form effective X-bonds with the side-chain hydroxyl oxygen of the IL-5Rα Thr21 residue and the backbone carbonyl oxygen of Ala66 residue, respectively. Binding assays observed that I-substitution at the 5 position and Br-substitution at the 6 position can result in two potent halogenated peptides, [5I]AF17121 and [6Br]AF17121, which are improved by 1.6-fold and 3.5-fold relative to the native AF17121, respectively. 5I/6Br-double substitution, resulting in [5I/6Br]AF17121, can further enhance the peptide affinity by 7.5-fold. Structural analysis revealed that the X-bond stemming from 6Br-substitution is also involved in an orthogonal interaction system with a H-bond; they share a common backbone carbonyl oxygen acceptor of IL-5Rα Ala66 residue and exhibit a significant synergistic effect between them.

Follow-up survey of general practitioners in Zhejiang Province post-completion of position transition training in 2017-2020.

BACKGROUND: Position transition training for general practitioners in Zhejiang Province started in 2017 and has since been held once a year. By the beginning of 2022, four training sessions were completed. The purpose of this survey was to establish the current situation of trainees after their graduation and provide reference for the evaluation of the training effect. METHODS: Of the 738 trainees who completed the training, 253 were contacted and followed up. A self-designed questionnaire was used to conduct the survey through online filling in. The content included questions to elucidate the following information: whereabouts after the training, registration as a general practitioner, undertaken general practice teaching and scientific research work, current occupational environment, improvement of post competence after receiving position transition training, willingness to complete survey, willingness to participate in future training programs, etc. RESULTS: A number of 253 valid questionnaires were collected with a recovery rate of 100%. Notably, 93.68% of the participants successfully completed their training and obtained the Training Certificate of General Practitioners. Further, 83.4% were registered as general practitioners, 82.94% of which added on the basis of the original registered scope of practice. Currently, most of them work in primary health care institutions, primarily occupied with medical treatment, chronic disease management, COVID-19 prevention and control, health education, and prevention and health care. Of them, 27.01% were currently undertaking teaching work, and only 3.32% of them were conducting scientific research work related to general practice. The overall satisfaction of the trainees in the three theoretical training bases was above 90%, with no statistically significant difference among them (P > 0.05). Importantly, 84.11% of the followed-up personnel hoped to continue to participate in similar training in the future to improve their general practitioner core competences. CONCLUSION: The position transition training in Zhejiang Province has achieved good results, but the details of training and the implementation of policies in individual regions need to be improved. Most of the graduates were willing to continue their education, especially in general practitioners with special interests.