A natural compound once deemed unusable as a drug repurposed to treat amoebiasis — Nagoya University establishes new microorganism-based synthesis method

A research team led by Associate Professor Yuta Tsunematsu from the Graduate School of Bioagricultural Sciences at Nagoya University, working jointly with Senior Researcher Yumiko Saito-Nakano from the Department of Parasitology, National Institute of Infectious Diseases, Japan Institute for Health Security, Associate Professor Ryota Shizu from the University of Shizuoka, Professor Tomoyoshi Nozaki from the Graduate School of Medicine at the University of Tokyo and Associate Professor Yuji Sumii from the Nagoya Institute of Technology, has established a novel drug discovery method called chem-bio hybrid synthesis that uses microorganisms, and successfully developed promising drug candidates for amoebiasis. The newly established method is expected to be applicable to the development of new drugs not only for amoebiasis but also for a wide range of infectious diseases and intractable conditions. The results were published in the Journal of the American Chemical Society.

Amoebiasis is a protozoan infection that affects large numbers of patients, particularly in developing countries, and can be life-threatening in severe cases. Although several effective treatments are known, concerns have been raised about side effects and drug resistance. The research group focused on the natural compound ovalicin, which shows exceptionally strong activity against Entamoeba histolytica. However, this compound degrades rapidly in the body, making it difficult to use as a medicine.

The research group investigated the shortcomings of ovalicin and found that rapid degradation by hepatic metabolic enzymes following administration is the primary factor limiting its therapeutic efficacy.

The researchers then took a different approach: rather than relying solely on the conventional semi-synthesis method of chemically modifying a natural product after it has been produced, they adopted a synthetic biology strategy that involves understanding and redesigning the biosynthetic machinery by which microorganisms produce natural products. Specifically, they engineered recombinant microorganisms to produce non-natural variants of the compound that already incorporate a substructure (a secondary hydroxyl group) amenable to subsequent chemical modification, and then selectively rewrote only the necessary portions through chemistry. This new approach, called "chem-bio hybrid synthesis," makes it possible to improve in vivo stability and safety, which are critical for drugs, without compromising the potency of complex natural products.

Using this method, the researchers systematically designed and synthesized approximately 30 improved compounds and identified a set of candidates that maintained strong anti-amoebic activity while being resistant to degradation in animals and exhibiting low toxicity. Animal experiments were then conducted on two optimized compounds that were selected from among the 30 compounds —YOK24 and NS-181. The two compounds demonstrated high therapeutic efficacy via either subcutaneous injection or oral administration in a hamster model of amoebic liver abscess, with complete resolution of the lesions confirmed.

This study demonstrates that by combining the biosynthetic capacity of microorganisms with the flexibility of chemical synthesis, natural products long regarded as "effective but undruggable" can be redesigned into forms suitable for therapeutic development. Beyond the creation of drug candidates for amoebiasis, the approach is expected to serve as a broadly applicable conceptual and technical platform for redesigning complex natural products to meet the requirements of drug discovery, with potential applications across a wide range of infectious diseases and intractable conditions.

Journal Information
Publication: Journal of the American Chemical Society
Title: Chem-Bio Hybrid Synthesis Enables Reengineering of Natural Product-Based Methionine Aminopeptidase 2 Inhibitors for Treating Amebiasis
DOI: 10.1021/jacs.5c18554