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Dr. Martin Safo

Institute for Structural Biology, Drug Discovery and Development, and the Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, VA

November 2nd, 2018 – Fall Seminar

Time and Location: Noon in Meyerhoff Chemistry, Room 120

Host: Dr. Songon An

 

Harnessing the Allosteric Property of Hemoglobin to Design Antisickling Agents for the Treatment of Sickle Cell Disease

Sickle cell disease (SCD) is the most common inherited hematologic disorder, affecting millions worldwide. The primary pathophysiology of SCD involves polymerization of sickle hemoglobin (Hb S) and sickling of red blood cells (RBC) under low O2 saturation that is exacerbated by sickle Hb low affinity for oxygen, presumably due to high concentration of 2,3-diphosphoglycerate and/or sphingosine phosphate in sickle RBC. This pathological process can be mitigated by increasing the oxygen affinity of Hb S, by shifting the allosteric equilibrium of Hb to the high-O2-affinity R-state. Covalent binding effectors of Hb, such as aromatic aldehydes, thiols, isothiocyanates, and Michael addition acceptors exhibit these pharmacologic properties. However, their development as therapeutic agents has been marked by several challenges e.g., non-specific binding, possible off-target toxicities, large therapeutic dose requirements, and, in the case of aldehydes, rapid metabolism in-vivo by aldehyde dehydrogenase (ALDH) and aldehyde oxidase (AO). Current investigations are increasingly focused on aromatic aldehydes, which form Schiff-base bonding with the N-terminal αVal1 nitrogen of Hb, and through several interactions link the two α-subunits to stabilize the R-state and increase Hb affinity for O2. Notable aldehydes studied in humans are vanillin and Valeresol (Phase I), and Tucaresol (Phase II). Vanillin and Valeresol exhibited low potency and/or poor oral bioavailability, while Tucaresol – although possessing favorable human pharmacokinetic properties – caused immune-mediated toxicity.

Our early preclinical studies and subsequent promising reports from a Phase I/II study with 5-HMF renewed optimism for this line of research, leading to investigators in both academia and industry to investigate molecules that share the same general mechanism of action. One such compound, GBT-440 developed recently by Global Blood Therapeutics, has demonstrated the principle that these molecules can bind to Hb with high specificity, mitigating some of the off-target binding concerns. GBT-440, which also exhibits good oral bioavailability and pharmacodynamic properties, is currently undergoing Phase III studies for the treatment of SCD.

Based on our original investigations on the antisickling properties of vanillin and 5-HMF, our group has rationally designed and synthesized several novel derivatives that exhibit significantly enhanced in-vitro/in-vivo pharmacologic activities; some of these compounds, in addition to the primary mechanism of increasing Hb affinity for O2 also directly destabilizes the Hb S polymer. Several of the compounds, e.g. VZHE-039, PP-6, PP-10, PP-14 are in advanced stages of study.