Year: 2026
Type: article
Abstract: Artemisinin and Yingzhaosu A (YZSA), two endoperoxide-containing natural products with antimalarial activity discovered through China's historic 523 Project, have long been the focus of global antimalarial research. Many scientific studies have proposed that their endoperoxide bridges are activated by heme (not hemoglobin) to generate active carbon radicals, which subsequently eliminate the parasite. However, we discovered that X-2b, a YZSA-structured turn-on fluorescent probe previously reported by our group, exhibited stronger reactivity toward hemoglobin than toward heme, a finding that prompted us to revisit and refine our previously reported conclusions. Herein, we present a systematic investigation into the reactivity of several representative endoperoxide-containing compounds toward heme and hemoglobin. The investigated endoperoxides show distinct reactivity toward heme versus hemoglobin. Notably, compounds showing high reactivity toward hemoglobin display diminished antimalarial activity. This study challenges the prevailing mechanistic paradigm and sheds new light on the mode of action of endoperoxide-containing antimalarials.
Source: ACS Omega
Language: English
Topic: Malaria Research and Control
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $1,935
Award: G6530602460
OpenAlex ID: W7214065098