Design, Synthesis, and Antisickling Investigation of a Nitric Oxide-Releasing Prodrug of 5HMF for the Treatment of Sickle Cell Disease.
Design, Synthesis, and Antisickling Investigation of a Nitric Oxide-Releasing Prodrug of 5HMF for the Treatment of Sickle Cell Disease.
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DOI：
10.3390/biom12050696
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发表时间：
2022-05-12
期刊：
影响因子：
5.5
通讯作者：
Safo, Martin K.
中科院分区：
文献类型：
--
作者：
Alhashimi, Rana T.;Ghatge, Mohini S.;Donkor, Akua K.;Deshpande, Tanvi M.;Anabaraonye, Nancy;Alramadhani, Dina;Danso-Danquah, Richmond;Huang, Boshi;Zhang, Yan;Musayev, Faik N.;Abdulmalik, Osheiza;Safo, Martin K.
5-羟基糠醛（5 HMF）是血红蛋白（Hb）的变构效应物，具有增加Hb对氧的亲和力的能力，其在体外和体内的抗镰状细胞作用以及在人类中用于治疗镰状细胞病（SCD）已被广泛研究。SCD的下游病理生理学之一是一氧化氮（NO）缺乏，因此已知增加NO（生物）可用性可减轻SCD症状的严重性。我们报道了一种释放NO的前体药物5 HMF（5 HMF-NO）的合成，该前体药物在体内有望生物转化为5 HMF和NO，并具有相应的治疗活性。体外研究表明，当与全血孵育时，5 HMF-NO释放NO，正如预期的那样。当与镰状血孵育时，5 HMF-NO与Hb形成希夫碱加合物，增加Hb对氧的亲和力，并防止缺氧诱导的红细胞镰状化，在1 mM浓度下分别为16%，10%和27%，而5 HMF为21%，18%和21%。5 HMF-NO与Hb的晶体结构表明，5 HMF-NO与未配体（脱氧）Hb结合，而水解产物5 HMF与配体（碳一氧基连接）Hb结合。我们从这个概念验证研究中的发现表明，将NO供体基团并入5 HMF和类似分子可能是治疗SCD的一种新的有益策略，并需要进一步详细的体内研究。
5-hydroxyfurfural (5HMF), an allosteric effector of hemoglobin (Hb) with an ability to increase Hb affinity for oxygen has been studied extensively for its antisickling effect in vitro and in vivo, and in humans for the treatment of sickle cell disease (SCD). One of the downstream pathophysiologies of SCD is nitric oxide (NO) deficiency, therefore increasing NO (bio)availability is known to mitigate the severity of SCD symptoms. We report the synthesis of an NO-releasing prodrug of 5HMF (5HMF-NO), which in vivo, is expected to be bio-transformed into 5HMF and NO, with concomitant therapeutic activities. In vitro studies showed that when incubated with whole blood, 5HMF-NO releases NO, as anticipated. When incubated with sickle blood, 5HMF-NO formed Schiff base adduct with Hb, increased Hb affinity for oxygen, and prevented hypoxia-induced erythrocyte sickling, which at 1 mM concentration were 16%, 10% and 27%, respectively, compared to 21%, 18% and 21% for 5HMF. Crystal structures of 5HMF-NO with Hb showed 5HMF-NO bound to unliganded (deoxygenated) Hb, while the hydrolyzed product, 5HMF bound to liganded (carbonmonoxy-ligated) Hb. Our findings from this proof-of-concept study suggest that the incorporation of NO donor group to 5HMF and analogous molecules could be a novel beneficial strategy to treat SCD and warrants further detailed in vivo studies.
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DOI：
10.1152/ajpheart.00665.2010
发表时间：
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影响因子：
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