Jiang Lubin Group discovered a new antimalarial drug target
Recently, Professor Jiang Lubin Group from Institut Pasteur of Shanghai cooperated with Professor Li Jian Group from East China University of Science and Technology and published a series of research papers about the latest research results of the development of new antimalarial drugs in Journal of Medicinal Chemistry (February 4, 2021), Cell Discovery (December 11, 2020) and Chinese Chemical Letters (December 13, 2020).
Malaria is one of the three major infectious diseases in the world. P. falciparum the most pathogenic plasmodium species causes hundreds of millions of clinical infections and causes nearly 500,000 deaths every year around the world. Due to the lack of an effective vaccine, the main treatment for malaria is still the artemisinin-based combination therapy. However, more and more drug-resistant P. falciparum strains have appeared, all first-line antimalarial drugs, including artemisinin, have developed clinical resistance and are spreading globally. Moreover, including artemisinin, the existing antimalarial drugs are mainly effective against the asexual stage parasites and there is no effective drug against other stage parasites right now (such as liver stage and sexual stage parasites). In the post-artemisinin era, new multi-stage antimalarial drugs with new targets are a hot and difficult point in international antimalaria research.
Since Professor Jiang Lubin worked full-time at Institut Pasteur of Shanghai in February 2012, he focused on the major strategic needs of the country’s “One Belt One Road” initiative in scientific and technological diplomacy with Southeast Asia and Africa and established a scientific research team with "Plasmodium Epigenetics" as the main research direction. Through the self-established high-throughput drug screening platform and combined with the epigenetic inhibitor compound library, the research team successfully screened a multi-stage small molecule antimalarial drug candidate (JL01) and successfully demonstrated that histone deacetylase PfHDAC1 is the drug target of JL01 by using the original epigenetic gene editing technology. Currently, the JL01 malaria treatment project has successfully entered preclinical research.
Based on the previous works above, Professor Jiang Lubin group cooperated with Professor Li Jian group and systematically optimized the compound structure of JL01 for better antimalarial activity and safety. In past two years, more than 300 derivates have been synthesized. After comprehensive evaluation of pharmacodynamics and safety experiments, three original compounds with better antimalarial activity and safety were finally obtained (11, 8, JX21108). The three recently published articles have systematically demonstrated that the newly developed antimalarial drug candidates have very effective antimalarial activity against the asexual stage, liver stage and the gametocyte stage parasites. In particular, these three lead compounds have good antimalarial activity against various drug-resistant P. falciparum clinical strains. The series research works not only provide new potential drug candidates for malaria prevention and treatment, but also provide new targets and strategies for the development of antimalarial drugs. More importantly, due to the multi-stage antimalarial activity of the series compounds, the success of these compounds in subsequent clinical trials will expected to achieve the combination of malaria treatment and transmission blocking for the first time.
This series work was mainly completed by Huang Zhenghui, the postdoctoral fellow from Institut Pasteur of Shanghai, Li Ruoxi, Ling Dazheng, Wang Xijiong, the doctoral candidate from East China University of Science and Technology, Tang Tongke, the doctoral candidate from Shanghai University of Science and Technology, and Xu Dandan, a joint graduate student from Bengbu Medical College. Professor Jiang Lubin and postdoctoral Huang Zhenghui from Institut Pasteur of Shanghai, Professor Li Jian and associate researcher Li Xiaokang from East China University of Science and Technology are the co-corresponding authors of these three published papers.
The series researches were supported by the National K&D Program of the Ministry of Science and Technology, the National Science and Technology Major Project, the National Natural Science Foundation of China, the key regional project of the Chinese Academy of Sciences for Science and Technology for Economic and Social Development (STS), and the Key Collaborative Research Program of the Alliances of International Science Organization (ANSO).
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