Related Experiment Video
Updated: Jul 10, 2025
Development of a Backbone Cyclic Peptide Library as Potential Antiparasitic Therapeutics Using Microwave Irradiation
Published on: January 26, 2016
Cyclic Peptides as Aggregation Inhibitors for Sickle Cell Disease
Vasco Neto1, Bruno Lourenço Victor1, Nuno Galamba1
1Biosystems and Integrative Sciences Institute, Faculdade de Ciências da Universidade de Lisboa, Edifício C8, Campo Grande 1749-016, Lisboa, Portugal.
Insights
New cyclic peptides (CPs) show potential for treating sickle cell disease (SCD). These CPs block deoxyhemoglobin S (HbS) aggregation, which causes red blood cells to sickle, offering a promising therapeutic strategy for SCD.
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.
Abstract:
Sickle cell disease is a missense genetic disorder characterized by the aggregation of deoxy-HbS into helical fibers that distort erythrocytes into a sickle-like shape. Herein, we investigate, through molecular dynamics, the effect of nine 5-mer cyclic peptides (CPs), tailor-designed to block key lateral contacts of the fibers. Our results show that the CPs bind orthogonally to the main HbS pocket involved in the latter contacts, with some revealing exceedingly long residence times. These CPs display moderate to high specificity, exhibiting molecular recognition events even at a HbS/CP (1:1) ratio. A much lower HbS-CP binding free energy, longer residence times, and higher specificity are also found relative to a previously reported CP with modest in vitro antisickling activity. These results indicate that some of these CPs have the potential to reduce the concentration of aggregation-competent deoxy-HbS, precluding or delaying the formation of lateral contact at the homogeneous nucleation stage.
Related Concept Videos
02:41Protein Complex Assembly
Many viruses self-assemble into a fully functional unit using the infected host cell to...
03:03Amyloid Fibrils
Amyloid deposits were observed as early as 1639 in the liver and the spleen. In 1854, Rudolph Virchow performed iodine staining,...