Cantini Francesca, Calderone Vito, Di Cesare Mannelli Lorenzo, Korsak Magdalena, Gonnelli Leonardo, Francesconi Oscar, Ghelardini Carla, Banci Lucia, Nativi Cristina
Dipartimento di Chimica "Ugo Schiff", University of Florence, via della Lastruccia, 3-13 50019 Sesto Fiorentino (FI), Italy.
CERM, University of Florence, via L. Sacconi, 6, 50019 Sesto Fiorentino (FI), Italy.
ACS Med Chem Lett. 2018 Oct 1;9(11):1094-1098. doi: 10.1021/acsmedchemlett.8b00199. eCollection 2018 Nov 8.
The formation of amorphous protein aggregates containing human superoxide dismutase (hSOD1) is thought to be involved in amyotrophic lateral sclerosis onset. -Platin inhibits the oligomerization of apo hSOD1, but its toxicity precludes any possible use in therapy. Herein, we propose a less toxic platinum complex, namely oxa/-platin, as hSOD1 antiaggregation lead compound. Oxa/-platin is able to interact with hSOD1 in the disulfide oxidized apo form by binding cysteine 111 (Cys111). The mild neurotoxic phenomena induced in vitro and in vivo by oxa/-platin can be successfully reverted by using lypoyl derivatives, which do not interfere with the antiaggregation properties of the platin derivative.
含有人类超氧化物歧化酶（hSOD1）的无定形蛋白质聚集体的形成被认为与肌萎缩侧索硬化症的发病有关。顺铂可抑制脱辅基hSOD1的寡聚化，但其毒性排除了其在治疗中的任何可能用途。在此，我们提出一种毒性较小的铂配合物，即奥沙铂，作为hSOD1抗聚集先导化合物。奥沙铂能够通过结合半胱氨酸111（Cys111）与二硫键氧化的脱辅基形式的hSOD1相互作用。使用硫辛酸衍生物可以成功逆转奥沙铂在体外和体内诱导的轻度神经毒性现象，而硫辛酸衍生物不会干扰铂衍生物的抗聚集特性。
