title: Crystallographic analysis of human hemoglobin elucidates the structural basis of the potent and dual antisickling activity of pyridyl derivatives of vanillin.
abstract: Vanillin has previously been studied clinically as an antisickling agent to treat sickle-cell disease. In vitro investigations with pyridyl derivatives of vanillin, including INN-312 and INN-298, showed as much as a 90-fold increase in antisickling activity compared with vanillin. The compounds preferentially bind to and modify sickle hemoglobin (Hb S) to increase the affinity of Hb for oxygen. INN-312 also led to a considerable increase in the solubility of deoxygenated Hb S under completely deoxygenated conditions. Crystallographic studies of normal human Hb with INN-312 and INN-298 showed that the compounds form Schiff-base adducts with the N-terminus of the α-subunits to constrain the liganded (or relaxed-state) Hb conformation relative to the unliganded (or tense-state) Hb conformation. Interestingly, while INN-298 binds and directs its meta-positioned pyridine-methoxy moiety (relative to the aldehyde moiety) further down the central water cavity of the protein, that of INN-312, which is ortho to the aldehyde, extends towards the surface of the protein. These studies suggest that these compounds may act to prevent sickling of SS cells by increasing the fraction of the soluble high-affinity Hb S and/or by stereospecific inhibition of deoxygenated Hb S polymerization.
authors.affiliation: Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Osheiza
authors.initials: O
authors.lastname: Abdulmalik
authors.forename: Mohini S
authors.initials: MS
authors.lastname: Ghatge
authors.forename: Faik N
authors.initials: FN
authors.lastname: Musayev
authors.forename: Apurvasena
authors.initials: A
authors.lastname: Parikh
authors.forename: Qiukan
authors.initials: Q
authors.lastname: Chen
authors.forename: Jisheng
authors.initials: J
authors.lastname: Yang
authors.forename: Ijeoma
authors.initials: I
authors.lastname: Nnamani
authors.forename: Richmond
authors.initials: R
authors.lastname: Danso-Danquah
authors.forename: Dorothy N
authors.initials: DN
authors.lastname: Eseonu
authors.forename: Toshio
authors.initials: T
authors.lastname: Asakura
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Abraham
authors.forename: Jurgen
authors.initials: J
authors.lastname: Venitz
authors.forename: Martin K
authors.initials: MK
authors.lastname: Safo
mesh_terms: D000755:Anemia, Sickle Cell / Q000188:drug therapy* / Q000378:metabolism; D000986:Antisickling Agents / Q000737:chemistry* / Q000494:pharmacology; D001547:Benzaldehydes / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D003460:Crystallization; D018360:Crystallography, X-Ray; D006451:Hemoglobin, Sickle / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D010100:Oxygen / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D011487:Protein Conformation / Q000187:drug effects; D011725:Pyridines / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D012545:Schiff Bases / Q000737:chemistry; D012995:Solubility / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D000986:Antisickling Agents; D001547:Benzaldehydes; D006451:Hemoglobin, Sickle; D011725:Pyridines; D012545:Schiff Bases; C100058:vanillin; D010100:Oxygen
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