Sickle cell disease is an inherited disorder of hemoglobin (Hb). During a sickle cell crisis, deoxygenated sickle hemoglobin (deoxyHbS) polymerizes to form fibers in red blood cells (RBCs), causing the cells to adopt "sickled" shapes. Using small molecules to increase the affinity of Hb for oxygen is a potential approach to treating sickle cell disease, because oxygenated Hb interferes with the polymerization of deoxyHbS. We have identified a triazole disulfide compound (4,4'-di(1,2,3-triazolyl)disulfide, designated TD-3), which increases the affinity of Hb for oxygen. The crystal structures of carboxy- and deoxy-forms of human adult Hb (HbA), each complexed with TD-3, revealed that one molecule of the monomeric thiol form of TD-3 (5-mercapto-1H-1,2,3-triazole, designated MT-3) forms a disulfide bond with β-Cys93, which inhibits the salt-bridge formation between β-Asp94 and β-His146. This inhibition of salt bridge formation stabilizes the R-state and destabilizes the T-state of Hb, resulting in reduced magnitude of the Bohr effect and increased affinity of Hb for oxygen. Intravenous administration of TD-3 (100 mg/kg) to C57BL/6 mice increased the affinity of murine Hb for oxygen, and the mice did not appear to be adversely affected by the drug. TD-3 reduced in vitro hypoxia-induced sickling of human sickle RBCs. The percentage of sickled RBCs and the P50 of human SS RBCs by TD-3 were inversely correlated with the fraction of Hb modified by TD-3. Our study shows that TD-3, and possibly other triazole disulfide compounds that bind to Hb β-Cys93, may provide new treatment options for patients with sickle cell disease.

中文翻译：

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三唑二硫化物化合物增加了血红蛋白对氧气的亲和力，并减少了人类镰状细胞的ick病。

镰状细胞病是血红蛋白（Hb）的遗传性疾病。在镰状细胞危机期间，脱氧的镰状血红蛋白（deoxyHbS）聚合形成红血球（RBC）中的纤维，导致细胞呈“带刺”的形状。使用小分子增加Hb对氧的亲和力是治疗镰状细胞疾病的一种潜在方法，因为氧化的Hb会干扰脱氧HbS的聚合。我们已经确定了三唑二硫化物（4,4'-二（1,2,3-三唑基）二硫化物，命名为TD-3），它​​增加了Hb对氧的亲和力。分别与TD-3复合的人类成年Hb（HbA）的羧基和脱氧形式的晶体结构表明，一分子的TD-3单体硫醇形式（5-mercapto-1H-1,2,3 -三唑，称为MT-3）与β-Cys93形成二硫键，它抑制了β-Asp94和β-His146之间的盐桥形成。盐桥形成的这种抑制作用稳定了Hb的R状态并使T状态不稳定，从而导致玻尔效应的强度降低，并且Hb对氧的亲和力增加。向C57BL / 6小鼠静脉注射TD-3（100 mg / kg）可提高鼠类Hb对氧气的亲和力，并且小鼠似乎未受到药物的不利影响。TD-3减少了体外缺氧诱导的人类镰刀RBC的镰刀。TD-3对镰状红细胞的百分比和人类SS RBC的P50与TD-3修饰的Hb分数成反比。我们的研究表明，TD-3以及可能与Hbβ-Cys93结合的其他三唑二硫化物可能为镰状细胞病患者提供新的治疗选择。