Tags

Type your tag names separated by a space and hit enter

VZHE-039, a novel antisickling agent that prevents erythrocyte sickling under both hypoxic and anoxic conditions.
Sci Rep. 2020 11 20; 10(1):20277.SR

Abstract

Sickle cell disease (SCD) results from a hemoglobin (Hb) mutation βGlu6 → βVal6 that changes normal Hb (HbA) into sickle Hb (HbS). Under hypoxia, HbS polymerizes into rigid fibers, causing red blood cells (RBCs) to sickle; leading to numerous adverse pathological effects. The RBC sickling is made worse by the low oxygen (O2) affinity of HbS, due to elevated intra-RBC concentrations of the natural Hb effector, 2,3-diphosphoglycerate. This has prompted the development of Hb modifiers, such as aromatic aldehydes, with the intent of increasing Hb affinity for O2 with subsequent prevention of RBC sickling. One such molecule, Voxelotor was recently approved by U.S. FDA to treat SCD. Here we report results of a novel aromatic aldehyde, VZHE-039, that mimics both the O2-dependent and O2-independent antisickling properties of fetal hemoglobin. The latter mechanism of action-as elucidated through crystallographic and biological studies-is likely due to disruption of key intermolecular contacts necessary for stable HbS polymer formation. This dual antisickling mechanism, in addition to VZHE-039 metabolic stability, has translated into significantly enhanced and sustained pharmacologic activities. Finally, VZHE-039 showed no significant inhibition of several CYPs, demonstrated efficient RBC partitioning and high membrane permeability, and is not an efflux transporter (P-gp) substrate.

Links

PMC Free PDF

Authors+Show Affiliations

Abdulmalik O
Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA. abdulmalik@email.chop.edu.
Pagare PP
Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA, 23298, USA.
Huang B
Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA, 23298, USA.
Xu GG
Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA, 23298, USA.
Ghatge MS
Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA, 23298, USA. The Institute for Structural Biology, Drug Discovery and Development, School of Pharmacy, Virginia Commonwealth University, Richmond, VA, 23298, USA.
Xu X
Department of Pharmaceutics, Virginia Commonwealth University, Richmond, VA, 23298, USA.
Chen Q
Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.
Anabaraonye N
Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.
Musayev FN
Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA, 23298, USA. The Institute for Structural Biology, Drug Discovery and Development, School of Pharmacy, Virginia Commonwealth University, Richmond, VA, 23298, USA.
Omar AM
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, King Abdulaziz University, Alsulaymanyah, 21589, Jeddah, Saudi Arabia. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Al-Azhar University, Cairo, 11884, Egypt.
Venitz J
Department of Pharmaceutics, Virginia Commonwealth University, Richmond, VA, 23298, USA.
Zhang Y
Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA, 23298, USA. The Institute for Structural Biology, Drug Discovery and Development, School of Pharmacy, Virginia Commonwealth University, Richmond, VA, 23298, USA.
Safo MK
Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA, 23298, USA. msafo@vcu.edu. The Institute for Structural Biology, Drug Discovery and Development, School of Pharmacy, Virginia Commonwealth University, Richmond, VA, 23298, USA. msafo@vcu.edu.

MeSH

AdultAnemia, Sickle CellAntisickling AgentsCaco-2 CellsCell HypoxiaCrystallography, X-RayDrug Evaluation, PreclinicalErythrocytes, AbnormalHemoglobin, SickleHumansModels, MolecularOxygenProtein Multimerization

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

33219275

Citation

Abdulmalik, Osheiza, et al. "VZHE-039, a Novel Antisickling Agent That Prevents Erythrocyte Sickling Under Both Hypoxic and Anoxic Conditions." Scientific Reports, vol. 10, no. 1, 2020, p. 20277.
Abdulmalik O, Pagare PP, Huang B, et al. VZHE-039, a novel antisickling agent that prevents erythrocyte sickling under both hypoxic and anoxic conditions. Sci Rep. 2020;10(1):20277.
Abdulmalik, O., Pagare, P. P., Huang, B., Xu, G. G., Ghatge, M. S., Xu, X., Chen, Q., Anabaraonye, N., Musayev, F. N., Omar, A. M., Venitz, J., Zhang, Y., & Safo, M. K. (2020). VZHE-039, a novel antisickling agent that prevents erythrocyte sickling under both hypoxic and anoxic conditions. Scientific Reports, 10(1), 20277. https://doi.org/10.1038/s41598-020-77171-2
Abdulmalik O, et al. VZHE-039, a Novel Antisickling Agent That Prevents Erythrocyte Sickling Under Both Hypoxic and Anoxic Conditions. Sci Rep. 2020 11 20;10(1):20277. PubMed PMID: 33219275.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - VZHE-039, a novel antisickling agent that prevents erythrocyte sickling under both hypoxic and anoxic conditions. AU - Abdulmalik,Osheiza, AU - Pagare,Piyusha P, AU - Huang,Boshi, AU - Xu,Guoyan G, AU - Ghatge,Mohini S, AU - Xu,Xiaomeng, AU - Chen,Qiukan, AU - Anabaraonye,Nancy, AU - Musayev,Faik N, AU - Omar,Abdelsattar M, AU - Venitz,Jürgen, AU - Zhang,Yan, AU - Safo,Martin K, Y1 - 2020/11/20/ PY - 2020/08/26/received PY - 2020/11/06/accepted PY - 2020/11/21/entrez PY - 2020/11/22/pubmed PY - 2021/3/31/medline SP - 20277 EP - 20277 JF - Scientific reports JO - Sci Rep VL - 10 IS - 1 N2 - Sickle cell disease (SCD) results from a hemoglobin (Hb) mutation βGlu6 → βVal6 that changes normal Hb (HbA) into sickle Hb (HbS). Under hypoxia, HbS polymerizes into rigid fibers, causing red blood cells (RBCs) to sickle; leading to numerous adverse pathological effects. The RBC sickling is made worse by the low oxygen (O2) affinity of HbS, due to elevated intra-RBC concentrations of the natural Hb effector, 2,3-diphosphoglycerate. This has prompted the development of Hb modifiers, such as aromatic aldehydes, with the intent of increasing Hb affinity for O2 with subsequent prevention of RBC sickling. One such molecule, Voxelotor was recently approved by U.S. FDA to treat SCD. Here we report results of a novel aromatic aldehyde, VZHE-039, that mimics both the O2-dependent and O2-independent antisickling properties of fetal hemoglobin. The latter mechanism of action-as elucidated through crystallographic and biological studies-is likely due to disruption of key intermolecular contacts necessary for stable HbS polymer formation. This dual antisickling mechanism, in addition to VZHE-039 metabolic stability, has translated into significantly enhanced and sustained pharmacologic activities. Finally, VZHE-039 showed no significant inhibition of several CYPs, demonstrated efficient RBC partitioning and high membrane permeability, and is not an efflux transporter (P-gp) substrate. SN - 2045-2322 UR - https://www.unboundmedicine.com/medline/citation/33219275/VZHE_039_a_novel_antisickling_agent_that_prevents_erythrocyte_sickling_under_both_hypoxic_and_anoxic_conditions_ DB - PRIME DP - Unbound Medicine ER -