Drug Development for Hemoglobin Disorder and Hypoxia-related Diseases

Oxygen is the most 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. In the pandemic of COVID-19, many patients have suffered silent hypoxia nad 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 (deoxyHb) 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 in seeking for drug cadidates which can serve as potent 2,3-BPG substitutes to boost Hb oxygen transport function and to prevent or treat hypoxia-related diseases. By combinining 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 for effective Hb modulators to regulate the Hb oxygen affinity, with the goals to improve the cellular oxygenation, to treat acute hypoxia and to 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 becomes too low to meet the physiological demands. This set of study sheds new lights in developing new medical strategies to treat and/or prevent various Hb oxygen transport defect and hypoxia- related syndromes and diseases.

 

 

References:

1. 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)
2. 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)