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Publications

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Epublish 19 citations

PubMed: 33219275 DOI: 10.1038/s41598-020-77171-2

VZHE-039, a novel antisickling agent that prevents erythrocyte sickling under both hypoxic and anoxic conditions.

Sci Rep 10(1):20277

Authors: Osheiza Abdulmalik, Piyusha P Pagare, Boshi Huang, Guoyan G Xu, Mohini S Ghatge, Xiaomeng Xu, Qiukan Chen, Nancy Anabaraonye, Faik N Musayev, Abdelsattar M Omar, Jürgen Venitz, Yan Zhang, Martin K Safo

Affiliations

  • Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.
  • 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.
  • Department of Pharmaceutics, Virginia Commonwealth University, Richmond, VA, 23298, USA.
  • Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.
  • 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.
  • 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.
  • 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.

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 (O) 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 O 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 O-dependent and O-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.

MeSH

Erythrocytes, Aldehydes, Polymers, Cells, Hemoglobins, 2,3-Diphosphoglycerate

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