Modulating hemoglobin allostery for treatment of sickle cell disease: current progress and intellectual property

ABSTRACT

Introduction

Sickle cell disease (SCD) is a debilitating inherited disorder that affects millions worldwide. Four novel SCD therapeutics have been approved, including the hemoglobin (Hb) modulator Voxelotor.

Areas Covered

This review provides an overview of discovery efforts toward modulating Hb allosteric behavior as a treatment for SCD, with a focus on aromatic aldehydes that increase Hb oxygen affinity to prevent the primary pathophysiology of hypoxia-induce erythrocyte sickling.

Expert Opinion

The quest to develop small molecules, especially aromatic aldehydes, to modulate Hb allosteric properties for SCD began in the 1970s; however, early promise was dogged by concerns that stalled support for research efforts. Persistent efforts eventually culminated in the discovery of the anti-sickling agent 5-HMF in the 2000s, and reinvigorated interest that led to the discovery of vanillin analogs, including Voxelotor, the first FDA approved Hb modulator for the treatment of SCD. With burgeoning interest in the field of Hb modulation, there is a growing landscape of intellectual property, including drug candidates at various stages of preclinical and clinical investigations. Hb modulators could provide not only the best chance for a highly effective oral therapy for SCD, especially in the under-developed world, but also a way to treat a variety of other human conditions.

KEYWORDS:

• Sickle cell disease
• hemoglobin
• oxygen affinity
• aromatic aldehydes
• Hb modulators
• allosteric effectors
• anti-sickling agents
• red blood cells
• polymerization

Article Highlights

• Sickle cell disease (SCD), the most common inherited hematologic disorder, occurs because of a single point mutation of βGlu6 in normal hemoglobin (HbA) to βVal6 in sickle hemoglobin (HbS).

• SCD is characterized by polymerization of HbS and sickling of red blood cells (RBCs), leading to several other pathophysiologies, including vaso-occlusion, hemolytic anemia, stroke, pain crisis, and organ damage.

• Much of the early drug discovery research for SCD was performed by Max Perutz, Don Abraham, and Irvine Klotz, which laid important foundation for subsequent drug discovery and development.

• Aromatic aldehydes are promising new clinical candidates that directly prevent the primary pathophysiology of hypoxia-induced HbS polymerization and erythrocyte sickling by increasing Hb oxygen affinity. One such compound, Voxelotor was recently approved for SCD treatment.

• In the opinion of these authors, Hb modulators, such as aromatic aldehydes could provide not only the best chance for a highly effective oral therapy for SCD, especially in the under-developed world, but also a way to treat a variety of other human conditions.

Acknowledgments

This article is dedicated to the memory of Don Abraham, a pioneer in sickle cell drug discovery.

Declaration of interests

Virginia Commonwealth University and some of the authors have patents related to several of the molecules mentioned in the review. Some of these compounds have been licensed over the years to several companies, including AesRx, Baxalta, Shire, Takeda, and Illexcor Therapeutics for the development to treat SCD. MK Safo and A Fleischman are co-owners of Illexcor Therapeutics which has licensed and developeing some of the compounds. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This paper was funded by NIH grants: [R61HL156158, NHLBI], [R01MD009124, NIMHD], [S10OD021756, OD].