More of the same? Voxelotor spawns a successor, but on what success does it build?

Frank A Ferrone

doi:10.1111/bjh.18785

Voxelotor is designed to impeded the polymerization of sickle haemoglobin. Although FDA-approved, its place in the treatment of sickle cell anaemia remains controversial. A report in this issue describes preliminary studies with a new drug GBT021601. Working in virtually the same fashion as voxelotor, the drug therefore immediately recapitulates on-going concern and controversy over the original agent. Oxygen delivery in humans is elegantly efficient. The sigmoidal oxygen saturation curve insures that as tissue pO2 drops, more oxygen can be delivered. Haemoglobin's exchange of a single oxygen molecule with solution is common and expected. The departure of a second O2 from Hb signals that local oxygen is becoming sparse, and as a result the Hb switches over to a state of lower oxygen affinity, anticipating future demands. The remaining two oxygen molecules can then dissociate with relative ease. Interaction between haemoglobin's subunits is responsible for this behaviour. Hb has two αβ dimers that can pack in different fashion depending on whether the molecule is in its high affinity (R) or low affinity (T) state. The T state is stabilized by eight salt bridges, six of which are between subunits and two of which involve the terminus of the α chain.1 The R-state packing is a ‘marriage of convenience’, with no special stabilization. Unsurprisingly, more than one R-state packing is known, and multiple packings are present in solution.2-4 In the absence of ligands, the T-state is some 64 000 times more abundant than the R thanks to these T-state bonds.5 Sickle cell anaemia is not primarily a disease of anaemic compromise, but one of circulatory catastrophe. A seemingly small mutation on the surface of the β chains allows HbS to form large and extensive arrays of polymers. These render the cell incompressible6 and make its escape from the capillaries problematic (a) if the polymers have formed during transit, and (b) if the exit to the venuoles is compromised by the presence of adherent cells that the usually pliable red cells could slip past but rigid sickled cells cannot.7 This clog of a single capillary is not an ischemic event of itself, since tissues are fed by multiple capillaries, and simulations we have conducted show that, relative to the rate of sickling, it is rare to recruit enough obstructed capillaries to draw down local O2 far enough for tissue damage, even though this is the eventual outcome. (Reese, Jiang and Ferrone, unpublished). O2 binding to the polymers can lead to polymer dissolution and thus reopen blocked capillaries. But polymers can only form when Hb is in the T-state.5, 8 Thus, the allosteric change subsequent to deoxygenation is required for polymerization. This motivates the therapeutic approach of restraining T-state formation so as to block polymer formation, which is the premise of voxelotor, and its successor GBT021601.9 By binding to the terminus of the α chain, the drug obstructs one of the salt bridges that stabilize the T structure, and by stretching across to the other α chain, also occludes its symmetry-related partner. (It is a bit of a misnomer to say that the R-state has become more stable.) But this strategy represents a trade-off, for in maintaining the R-state, the ingenious mechanism of enhanced haemoglobin O2 delivery is compromised (Figure 1).

More of the same? Voxelotor spawns a successor, but on what success does it build?

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More of the same? Voxelotor spawns a successor, but on what success does it build?

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