Cyclic Peptides as Aggregation Inhibitors for Sickle Cell Disease

Area of Science:

• Biochemistry
• Genetics
• Molecular Biology

Background:

• Sickle cell disease (SCD) is a missense genetic disorder.
• It is characterized by the aggregation of deoxyhemoglobin S (HbS) into helical fibers.
• This aggregation distorts erythrocytes into a sickle-like shape.

Purpose of the Study:

• To investigate the effect of nine tailor-designed 5-mer cyclic peptides (CPs).
• To determine if CPs can block key lateral contacts in HbS fibers.
• To evaluate the binding affinity, specificity, and residence times of CPs with HbS.

Main Methods:

• Molecular dynamics simulations were employed.
• The binding of nine 5-mer cyclic peptides (CPs) to HbS was investigated.
• Binding free energy, residence times, and specificity were analyzed.

Main Results:

• CPs bind orthogonally to the main HbS pocket involved in lateral contacts.
• Some CPs exhibited exceedingly long residence times.
• CPs displayed moderate to high specificity, even at a 1:1 HbS/CP ratio.
• Lower binding free energy and longer residence times were observed compared to a previously reported CP.

Conclusions:

• The studied CPs show potential for reducing aggregation-competent deoxy-HbS concentration.
• These CPs may preclude or delay the formation of lateral contacts during HbS aggregation.
• The findings suggest a promising therapeutic avenue for managing sickle cell disease by inhibiting HbS polymerization.