Optimizing drugs and establishing preclinical studies for the realization of infectious disease drug discovery

Regarding anti-ameba histolytica drugs, based on the structure-activity relationship of fumagillin derivatives synthesized so far, compounds will be synthesized with the main aim of separating efficacy and toxicity, and evaluate anti-ameba activity and cytotoxicity. This project will select several compounds among derivatives with excellent efficacy and low toxicity, and verify them by using a hamster model system. The antimalarial borrelidin derivative is similarly evaluated for antiprotozoal activity and toxicity. Derivatives with excellent selectivity are verified by a system using a murine model. For the search for compounds with anti-tuberculosis activity, the project will establish a high-throughput screening system (HTS) targeting coenzyme A biosynthesis CoABC, shikimate metabolism SK, etc. of M. tuberculosis. The project will further optimize the recombinant protein production method and assay system, and perform HTS of inhibitors from a library of compounds with known structures. In the search for compounds with anti-dengue activity, the project will establish an HTS system targeting dengue virus NS2B-NS3 and search for inhibitors from domestic microorganisms and plant extracts. Regarding the safety test, after structural optimization of the anti-higella and malaria active compound, several compounds are selected and initial in vitro safety test and initial pharmacokinetic test are carried out. Conduct exploratory research using natural resource libraries and synthetic compound libraries with the aim of discovering and providing seed compounds for novel tuberculosis drug discovery. technology transfer to Validation is performed on the structurally expanded anti-tuberculosis candidate derivatives. Exploratory research is carried out using natural resource libraries with the aim of discovering and providing seed compounds for new dengue drug discovery. The technology of the newly constructed dengue screening system will be transferred to Malaysia. The project will provide structural information to the in silico enzyme inhibitory activity evaluation system of the University of Malaya, optimize the structure of the discovered inhibitory compounds, and provide suggestions for synthetic development. Further in vitro validation of the expanded compound is performed. The project will conduct in vitro safety tests, in vivo toxicity tests, and pharmacokinetic tests in rats for antimalarial, Entamoeba histolytica, tuberculosis, and dengue drug candidate compounds, and transfer the safety test system technology to Indonesia. This research will focus on drug optimization and establishment of preclinical studies toward the realization of infectious disease drug discovery from microbial resources. In particular, the aim is to develop drugs for malaria, amebiasis dysentery, tuberculosis, and dengue up to preclinical testing. Specifically, (1) Efficacy and safety verification of drug candidates for malaria and Entamoeba histolytica, and anti-tuberculosis hit search, identification, drug efficacy and safety verification, (2) Anti-tuberculosis and anti-dengue hit search, identification, drug efficacy, and Safety verification, (3) synthesis and structural optimization of candidate compounds, and (4) safety and efficacy tests of candidate compounds. This fiscal year, the project will establish collaboration among four groups in Japan, and at the same time, prepare to form collaboration with joint research groups in Indonesia and Malaysia. Considering the impact of COVID-19, the project will hold multiple meetings via teleconference, e-mail, face-to-face, etc. to gain mutual understanding and consent regarding the sharing, transfer, etc. of goods and data.

Drug-based Strategies
Product Development

Apr 2020 — Mar 2026

$60,465

Japan