Adjou Karim Tarik, Simoneau Steve, Salès Nicole, Lamoury François, Dormont Dominique, Papy-Garcia Dulce, Barritault Denis, Deslys Jean-Philippe, Lasmézas Corinne Ida
CEA, DSV/DRM, 18 route du Panorama, BP6, 92265 Fontenay aux Roses Cedex, France.
OTR3 Sarl, 33 rue Pierre Brossolette, 94000 Créteil, France.
J Gen Virol. 2003 Sep;84(Pt 9):2595-2603. doi: 10.1099/vir.0.19073-0.
The accumulation of PrP(res), the protease-resistant abnormal form of the host-encoded cellular prion protein, PrP(C), plays a central role in transmissible spongiform encephalopathies. Human contamination by bovine spongiform encephalopathy (BSE) has propelled many scientific teams on a highway for anti-prion drug development. This study reports that heparan sulfate mimetics (HMs), developed originally for their effect on tissue regeneration, abolish prion propagation in scrapie-infected GT1 cells. PrP(res) does not reappear for up to 50 days post-treatment. When tested in vivo, one of these compounds, HM2602, hampered PrP(res) accumulation in scrapie- and BSE-infected mice and prolonged significantly the survival time of 263K scrapie-infected hamsters. Interestingly, HM2602 is an apparently less toxic and more potent inhibitor of PrP(res) accumulation than dextran sulfate 500, a molecule known to exhibit anti-prion properties in vivo. Kinetics of PrP(res) disappearance in vitro and unaffected PrP(C) levels during treatment suggest that HMs are able to block the conversion of PrP(C) into PrP(res). It is speculated that HMs act as competitors of endogenous heparan sulfates known to act as co-receptors for the prion protein. Since these molecules are particularly amenable to drug design, their anti-prion potential could be developed further and optimized for the treatment of prion diseases.
宿主编码的细胞朊病毒蛋白PrP(C)的蛋白酶抗性异常形式PrP(res)的积累在传染性海绵状脑病中起核心作用。牛海绵状脑病（BSE）对人类的感染促使许多科研团队走上了抗朊病毒药物研发的道路。本研究报告称，最初因其对组织再生的作用而开发的硫酸乙酰肝素模拟物（HMs）可消除瘙痒病感染的GT1细胞中的朊病毒传播。处理后长达50天PrP(res)都不会再次出现。在体内进行测试时，其中一种化合物HM2602可抑制瘙痒病和BSE感染小鼠体内PrP(res)的积累，并显著延长263K瘙痒病感染仓鼠的存活时间。有趣的是，与硫酸葡聚糖500相比，HM2602对PrP(res)积累的抑制作用毒性明显更低且更强，硫酸葡聚糖500是一种已知在体内具有抗朊病毒特性的分子。体外PrP(res)消失的动力学以及处理过程中PrP(C)水平未受影响表明，HMs能够阻断PrP(C)向PrP(res)的转化。据推测，HMs作为内源性硫酸乙酰肝素的竞争者发挥作用，已知内源性硫酸乙酰肝素可作为朊病毒蛋白的共受体。由于这些分子特别适合药物设计，它们的抗朊病毒潜力可以进一步开发并优化用于治疗朊病毒疾病。
