Oxygen is the essential compound in sustaining lives on Earth. Once inhaled, oxygen permeates through the alveoli by diffusion and enters into the blood circulation. Hemoglobin (Hb), the oxygen-carrying protein in erythrocytes, is then responsible for picking up oxygen and transporting it to various organs and peripheral tissues to assure the normal physiological functions of the organs and the peripheral tissues. Unfortunately, in the pandemic of COVID-19, many patients have suffered silent hypoxia and sudden death.
Hb is a hetero-tetramer (α2β2) comprised of two α and two β subunits, with each subunit containing a heme group and a globular protein. The heme iron lies out of the porphyrin plane when deoxygenated, with the quaternary structure of deoxygenated Hb (deoxy-Hb) resided in the low oxygen affinity "tense" (T) state. Upon oxygenation, the binding of oxygen to the heme iron pulls the iron into the porphyrin plane, which causes certain spatial constraints to destabilize the T state and triggers the oxygenated hemoglobin (oxyHb) to transform into the high oxygen affinity, "relaxed" (R) state. In addition to Hb itself, the endogenous Hb modulator, 2,3-bisphosphoglycerate (2,3-BPG), plays a determinant role in regulating Hb allostery. 2,3-BPG is essential to guide Hb to release oxygen properly, achieved by preferentially binding to the low-affinity T state of Hb to decrease its oxygen affinity. Though 2,3-BPG exists in erythrocytes with a relatively high in vivo concentration for normal adults (~ 5 to 8 mM), 2,3-BPG metabolism degrades chronically. Insufficient 2,3-BPG levels may lead to defect Hb oxygen transport, cellular hypoxia, and increased rates of various oxygen transport deficit induced-/related- morbidity.
The research team led by Prof. Chia C. Wang, Director of ASRC, has made great efforts in the past decade to seek drug candidates that can serve as potent 2,3-BPG substitutes to boost Hb oxygen transport function and prevent or treat hypoxia-related diseases. By combining spectroscopic and computational approaches, we have successfully identified a set of phthalide derivatives capable of promoting the oxygen transport function of Hb via allosterically stabilizing oxyHb in the low-affinity T state.
It has been an ongoing effort to seek effective Hb modulators to regulate the Hb oxygen affinity, improve cellular oxygenation, treat acute hypoxia, and prolong the shelf life of stored erythrocytes. In light of their pronounced Hb allosteric modulatory effects, the bioactive phthalide derivatives from AS appear promising to serve as 2,3-BPG functional substitutes/supplements to assist Hb in better releasing oxygen when the endogenous 2,3-BPG levels become too low to meet the physiological demands. Thus, this study set sheds new light on developing new medical strategies to treat and/or prevent various Hb oxygen transport defects and hypoxia-related syndromes and diseases.
- Chen, W.-R., Chou, C.-C., Wang, C.C.* (2019): Phthalides serve as potent modulators to boost the efficacy of fetal hemoglobin induction therapy for β-hemoglobinopathies. Blood Adv., 3, 1493-1498. (link)
- Chen, W.-R., Yu, Y., Zulfajri, M., Lin, P.-C., Wu, Z.-H., Chen, M.-S., Wang, C. C.* (2017): Phthalide derivatives from Angelica sinensis decrease oxygen affinity of hemoglobin: A new allosteric-modulating mechanism and potential use as 2,3-BPG substitutes. Sci. Rep. 7, 5504. (link)
This set of study has been been granted several patents of Taiwan and U.S.A. in treating hypoxia, blood diseases, Alzheimer and other non-Alzheimer neurodegenerative diseases, listed below:
1. Wang, C. C., Chen, W.-R. (2018): Method for enhancing the oxygen level of tissue cells as an alternative method for hyperbaric oxygen therapy. United States of America Patent (Patent No US 9,937,150 B2).
2. Wang, C. C., Chen, W.-R., (2018): Method for enhancing the oxygen level of tissue cells as an alternative method for hyperbaric oxygen therapy. Republic of China Patent (Patent No TW I643615 B).
3. Wang, C. C., Chen, W.-R. (2018): Use of phthalides in the preparation of medicinal composition for treating Alzheimer’s disease and 2,3-Biphosphoglycerate metabolism disorder induced morbidities. Republic of China Patent (Patent No TW I638655 B).4. Wang, C. C., Zulfajri, M., Yu, Y. (2018): A method for improving the oxygen-releasing ability of hemoglobin to organs and peripheral tissues in human bodies and a medication thereof. United States of America Patent (Patent No US 10,047,063 B2).
5. Wang, C. C., Chen, W.-R. (2017): Method for facilitating the oxygen release of hemoglobin-based blood substitutes. United States of America Patent (Patent No US 9,713,602 B1).
6. Wang, C. C., Zulfajri, M., Yu, Y. (2017): A method for improving the oxygen-releasing ability of hemoglobin to organs and peripheral tissues in human bodies and its medication mixture. Republic of China Patent (Patent No TW I602564 B).
7. Wang, C. C., Zulfajri, M., Yu, Y. (2016): A use of ferulic acid for manufacturing drugs for improving the oxygen-releasing ability of hemoglobin to organs and peripheral tissues in human bodies. Republic of China Patent (Patent No TW I532482 B).