Peptides are a particular molecule class with inherent attributes of some small-molecule drugs and macromolecular biologics,thereby inspiring continuous searches for peptides with therapeutic and/or agrochemical poten...Peptides are a particular molecule class with inherent attributes of some small-molecule drugs and macromolecular biologics,thereby inspiring continuous searches for peptides with therapeutic and/or agrochemical potentials.However,the success rate is decreasing,presumably because many interesting but less-abundant peptides are so scarce or labile that they are likely‘overlooked’during the characterization effort.Here,we present the biochemical characterization and druggability improvement of an unprecedented minor fungal RiPP(ribosomally synthesized and post-translationally modified peptide),named acalitide,by taking the relevant advantages of metabolomics approach and disulfide-bridged substructure which is more frequently imprinted in the marketed peptide drug molecules.Acalitide is biosynthetically unique in the macrotricyclization via two disulfide bridges and a protease(AcaB)-catalyzed lactamization of AcaA,an unprecedented precursor peptide.Such a biosynthetic logic was successfully re-edited for its sample supply renewal to facilitate the identification of the in vitro and in vivo antiparkinsonian efficacy of acalitide which was further confirmed safe and rendered brain-targetable by the liposome encapsulation strategy.Taken together,the work updates the mining strategy and biosynthetic complexity of RiPPs to unravel an antiparkinsonian drug candidate valuable for combating Parkinson’s disease that is globally prevailing in an alarming manner.展开更多
Background: Antiparkinsonian pharmacotherapy represents one of the most important expenses related to Parkinson’s disease. The application of generic drugs may help to reduce the economic burden of the disease;howeve...Background: Antiparkinsonian pharmacotherapy represents one of the most important expenses related to Parkinson’s disease. The application of generic drugs may help to reduce the economic burden of the disease;however, efficacy and safety of these products have been less studied. Objective: To investigate the efficacy and safety of generic rasagiline (Ralago?) from a clinical perspective. Methods: The Clinical Global Impression of Severity scale was used to rate the most important motor and non-motor symptoms at baseline and 12 weeks after the initiation of Ralago?. Patients also identified symptoms which were the main sources of their disability and distress in everyday life. Results: A total of 499 patients were enrolled (231 females, mean age: 73.2 ± 9.1 years, mean duration of disease: 3.6 ± 3.7 years). Of them, 486 patients completed the study protocol. Both motor and non-motor symptoms showed improvement during 12-week Ralago? treatment. Adverse events were rare, and the majority of them were not considered as serious. Conclusions: The generic rasagiline (Ralago?) is an effective and safe generic product.展开更多
Recent studies have shown that fibroblast transplantation can modify the activity of basal ganglia networks in models of Parkinson＇s disease. To determine its effects on parkinsonian motor symptoms, we performed auto...Recent studies have shown that fibroblast transplantation can modify the activity of basal ganglia networks in models of Parkinson＇s disease. To determine its effects on parkinsonian motor symptoms, we performed autologous dermal fibroblast transplantation into the internal pallidum （GPi） in two parkinsonian rhesus monkeys with stable levodopa- induced dyskinesias （LIDs）. Levodopa responses were assessed every week after transplantation for three months. A reduction of between 58% and 64% in total LIDs on the contralateral side was observed in both animals. No clear LID changes were observed on the ipsilateral side. These effects lasted the entire 3-month period in one monkey, but declined after 6-8 weeks in the other. The antiparkinsonian effects of levodopa did not diminish, The results of this pilot study indicate that fibroblast transplantation into the GPi may have beneficial effects on LIDs and warrant further investigation for potential therapeutic use.展开更多
基金co-financed by the NSFC(81991524,81991523,and 22193071,China)MOST grants(STI2030-Major Project-2022ZD0211804,China).
文摘Peptides are a particular molecule class with inherent attributes of some small-molecule drugs and macromolecular biologics,thereby inspiring continuous searches for peptides with therapeutic and/or agrochemical potentials.However,the success rate is decreasing,presumably because many interesting but less-abundant peptides are so scarce or labile that they are likely‘overlooked’during the characterization effort.Here,we present the biochemical characterization and druggability improvement of an unprecedented minor fungal RiPP(ribosomally synthesized and post-translationally modified peptide),named acalitide,by taking the relevant advantages of metabolomics approach and disulfide-bridged substructure which is more frequently imprinted in the marketed peptide drug molecules.Acalitide is biosynthetically unique in the macrotricyclization via two disulfide bridges and a protease(AcaB)-catalyzed lactamization of AcaA,an unprecedented precursor peptide.Such a biosynthetic logic was successfully re-edited for its sample supply renewal to facilitate the identification of the in vitro and in vivo antiparkinsonian efficacy of acalitide which was further confirmed safe and rendered brain-targetable by the liposome encapsulation strategy.Taken together,the work updates the mining strategy and biosynthetic complexity of RiPPs to unravel an antiparkinsonian drug candidate valuable for combating Parkinson’s disease that is globally prevailing in an alarming manner.
文摘Background: Antiparkinsonian pharmacotherapy represents one of the most important expenses related to Parkinson’s disease. The application of generic drugs may help to reduce the economic burden of the disease;however, efficacy and safety of these products have been less studied. Objective: To investigate the efficacy and safety of generic rasagiline (Ralago?) from a clinical perspective. Methods: The Clinical Global Impression of Severity scale was used to rate the most important motor and non-motor symptoms at baseline and 12 weeks after the initiation of Ralago?. Patients also identified symptoms which were the main sources of their disability and distress in everyday life. Results: A total of 499 patients were enrolled (231 females, mean age: 73.2 ± 9.1 years, mean duration of disease: 3.6 ± 3.7 years). Of them, 486 patients completed the study protocol. Both motor and non-motor symptoms showed improvement during 12-week Ralago? treatment. Adverse events were rare, and the majority of them were not considered as serious. Conclusions: The generic rasagiline (Ralago?) is an effective and safe generic product.
基金supported by grants from the National Institutes of Health (NS045962, NS073994, NCRR RR000165 and ORIP/OD OD011132)Forum Pharmaceuticals, Inc.Gene Graft, Ltd
文摘Recent studies have shown that fibroblast transplantation can modify the activity of basal ganglia networks in models of Parkinson＇s disease. To determine its effects on parkinsonian motor symptoms, we performed autologous dermal fibroblast transplantation into the internal pallidum （GPi） in two parkinsonian rhesus monkeys with stable levodopa- induced dyskinesias （LIDs）. Levodopa responses were assessed every week after transplantation for three months. A reduction of between 58% and 64% in total LIDs on the contralateral side was observed in both animals. No clear LID changes were observed on the ipsilateral side. These effects lasted the entire 3-month period in one monkey, but declined after 6-8 weeks in the other. The antiparkinsonian effects of levodopa did not diminish, The results of this pilot study indicate that fibroblast transplantation into the GPi may have beneficial effects on LIDs and warrant further investigation for potential therapeutic use.
