# HbS oligomers as a therapeutic target in sickle cell disease

> **NIH NIH R21** · UNIVERSITY OF MINNESOTA · 2020 · $224,713

## Abstract

The molecular origin of sickle cell disease (SCD) has been known since 1949. Despite this, the treatment
options for afflicted individuals remain limited to a few therapies that have widely variable and/or limited
efficacy. The dearth of therapies stems, at least in part, from a dearth of high throughput assays with which to
identify molecules that can inhibit sickle hemoglobin (HbS) polymerization. Here, we propose a BOLD
BIOENGINEERING approach to drug discovery in sickle cell using time resolved FRET detection of HbS
oligomers at sub-nucleating concentrations, which is sensitive to compounds that inhibit HbS interactions and
is compatible with high throughput screening (HTS). We have recently developed a novel, time-resolved (TR-
FRET) assay that allows direct detection of HbS oligomers and that is compatible with HTS. Thus, for the first
time, we have the tools to screen for compounds that inhibit HbS nucleation and polymerization. Moreover, this
assay is capable of identifying compounds that disrupt oligomer formation via direct competition with the
primary binding site or by allosterically modifying the HbS confirmation. In a pilot screen of a small library (one
thousand compounds) we have, for the first time, discovered lead compounds that eliminate HbS oligomers
and rescue whole blood from the sickle pathology. Thus, we are now in a position to perform a large-scale
campaign to discover and characterize lead compounds with the potential to transform the translation
landscape of SCD. In the proposed project, we will: (1) use TR-FRET to discover new small molecules that
inhibit in vitro HbS nucleation and (2) determine which subset of hit compounds are able to inhibit HbS
polymerization in whole blood under physiologic conditions. This work will serve as a proof of concept HTS
discovery compaign that will revolutionary for the field of SCD and will reveal new mechanisms for disrupting
HbS polymerization that could transform the landscape for therapy. Additionally, in the course of this work, we
will discover and validate new candidate small molecules that can inhibit HbS nucleation and polymerization
under physiologic conditions and may lead to desperately needed new clinical therapies for this terrible
disease.

## Key facts

- **NIH application ID:** 9954358
- **Project number:** 1R21HL152313-01
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** David Kevin Wood
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $224,713
- **Award type:** 1
- **Project period:** 2020-04-16 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9954358

## Citation

> US National Institutes of Health, RePORTER application 9954358, HbS oligomers as a therapeutic target in sickle cell disease (1R21HL152313-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9954358. Licensed CC0.

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