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

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

  • Sci Rep. 2020 Nov 20;10(1):20277. doi: 10.1038/s41598-020-77171-2.
Osheiza Abdulmalik 1,  Piyusha P Pagare 2,  Boshi Huang 2,  Guoyan G Xu 2,  Mohini S Ghatge 2 3,  Xiaomeng Xu 4,  Qiukan Chen 5,  Nancy Anabaraonye 5,  Faik N Musayev 2 3,  Abdelsattar M Omar 6 7,  Jürgen Venitz 4,  Yan Zhang 2 3,  Martin K Safo 8 9
Affiliations

Affiliations

  • 1 Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA. [email protected].
  • 2 Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA, 23298, USA.
  • 3 The Institute for Structural Biology, Drug Discovery and Development, School of Pharmacy, Virginia Commonwealth University, Richmond, VA, 23298, USA.
  • 4 Department of Pharmaceutics, Virginia Commonwealth University, Richmond, VA, 23298, USA.
  • 5 Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.
  • 6 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, King Abdulaziz University, Alsulaymanyah, 21589, Jeddah, Saudi Arabia.
  • 7 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Al-Azhar University, Cairo, 11884, Egypt.
  • 8 Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA, 23298, USA. [email protected].
  • 9 The Institute for Structural Biology, Drug Discovery and Development, School of Pharmacy, Virginia Commonwealth University, Richmond, VA, 23298, USA. [email protected].
PMID: 33219275 DOI: 10.1038/s41598-020-77171-2
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.

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