Rational Drug Design of Peptide-Based Therapies for Sickle Cell Disease

Abstract

Sickle cell disease (SCD) is a group of inherited disorders affecting red blood cells, which is caused by a single mutation that results in substitution of the amino acid valine for glutamic acid in the sixth position of the β-globin chain of hemoglobin. These mutant hemoglobin molecules, called hemoglobin S, can polymerize upon deoxygenation, causing erythrocytes to adopt a sickled form and to suffer hemolysis and vaso-occlusion. Until recently, only two drug therapies for SCD, which do not even fully address the manifestations of SCD, were approved by the United States (US) Food and Drug Administration. A third treatment was newly approved, while a monoclonal antibody preventing vaso-occlusive crises is also now available. The complex nature of SCD manifestations provides multiple critical points where drug discovery efforts can be and have been directed. These notwithstanding, the need for new therapeutic approaches remains high and one of the recent efforts includes developments aimed at inhibiting the polymerization of hemoglobin S. This review focuses on anti-sickling approaches using peptide-based inhibitors, ranging from individual amino acid dipeptides investigated 30-40 years ago up to more promising 12-and 15-mers under consideration in recent years.Molecules 2019, 24, 4551 2 of 23 with hemoglobin reduces HbS solubility and promotes polymerization, also called sickling [3,4]. This ultimately leads to hampered O 2 binding and transport, impaired erythrocyte morphology and interaction with endothelial surfaces [5,6], premature erythrocyte rupture and anemia, painful vaso-occlusive crisis, a general poor health, and, in many cases, death [7][8][9][10][11].Despite growing understanding of the polymerization of HbS and its effects on red blood cells (RBCs), until very recently, only two drugs-hydroxyurea and L-glutamine-were approved by the United States (US) Food and Drug Administration (FDA) for the management of SCD [12]. Hydroxyurea is the most widely employed drug treatment of sickle cell anemia in different age groups [13][14][15][16][17][18]. While its clinically observed efficacy has been attributed to different effects at the cellular level [19], the most important mechanism of action relates to its ability to induce the production of fetal hemoglobin (HbF), which does not polymerize, and to increase the total concentration of hemoglobin [20,21]. Hydroxyurea remains a viable treatment option for SCD, and the concern of toxicities associated with its administration has largely been limited to side effects that resolve with medication discontinuation [22][23][24][25][26]. There have, however, been certain reports of associated malignancies [27][28][29][30][31][32], but further investigations are needed to categorically confirm these [33]. L-glutamine is the second approved drug treatment [12,34]. While its mechanism of action is not known, and only suggested to involve a reduction of oxidative stress via elevation of the levels of reduced glutathione [35,36], it is clear that it has no effect on hemo...

Multiscale MD simulations of wild‐type and sickle hemoglobin aggregation

“…26 The figure is reproduced with permission from ref. 25 initiated from heme-containing crystal structures using CHARMM22* as force field for the proteins 41 and the TIP3P model for water. 42 The proteins were first studied in their monomeric states.…”

“…With pathological processes in SCD directly linked to the aggregation of HbS, having a working understanding of the structural and dynamical processes underlying protein aggregation is crucial 14 . First, this provides an understanding of the aggregation process in detail, which can then be exploited in rationally developing therapeutic strategies, including peptide‐based inhibitors that target HbS aggregation 25 . HbS aggregation, or polymerization, occurs via a double nucleation mechanism, 27–29 starting with an homogenous nucleation phase where HbS aggregates randomly.…”

“…14 First, this provides an understanding of the aggregation process in detail, which can then be exploited in rationally developing therapeutic strategies, including peptide-based inhibitors that target HbS aggregation. 25 HbS aggregation, or polymerization, occurs via a double nucleation mechanism, [27][28][29] starting with an homogenous nucleation phase where HbS aggregates randomly. This is followed by heterogeneous nucleation, where the rate of polymerization increases and new nuclei form on the already existing polymer strands derived from primary nucleation.…”

“…The His and Val residues are shown as sticks and are colored by atom name (C: yellow; N: blue; O: red). This figure is reproduced with permission 25 and uses PDB entry 5E6E 26 as HbS structure protein-protein interactions in the resulting aggregates are elucidated and their stability is further examined by all-atom simulations of the aggregates that were back mapped from the coarse-grained to the atomistic level. These simulations enable us to quantify the relative strengths of molecular contacts and identify protein-protein interaction hotspots between HbS molecules, which in future studies can be prioritized for aggregation inhibitor design.…”

Hoslundia oppositaand other Nigerian plants inhibit sickle hemoglobin polymerization and prevent erythrocyte sickling: a virtual screening-guided identification of bioactive plants

“…HbS polymerization within erythrocytes provokes an alteration in the functional shape of red cells from the normal spherical form into distorted shapes some of which resemble a sickle (Bisnu et al, 2013& Herrick, 1910. With the HbS molecule occupying a central position in disease development, it makes sense that efforts to evolve new leads for SCD management should, as a viable option, consider the inhibition of HbS polymerization both by small molecules (Ismaila O. Nurain, 2017) and larger molecular weight peptide-based inhibitors (Olubiyi et al, 2019). For instance, the recently FDA-approved voxelotor is a covalent modifier of HbS molecule and acts as an allosteric modulator stabilizing the hemoglobin molecule in its non-aggregating R-conformer (Vichinsky et al, 2019).…”