Anthrax LF Inhibitor Drug Based On Organosilanes

描述(由申请人提供)：硅烷二醇是首席研究员实验室首创的新型过渡态类似蛋白水解酶抑制剂。这些结构在低纳摩尔(NM)水平下是金属蛋白酶的有效抑制剂，并且能够以与非硅烷(商业)药物相当的速度穿过细胞膜。炭疽杆菌Lf是一种金属蛋白酶，也是炭疽毒素的来源。目前还没有对该酶的有效抑制剂进行描述。这项研究的初始阶段将利用已知的底物特性生产一种硅烷二醇抑制LF。第二阶段将从结构上改变这种抑制剂，以去除多肽特性，从而改善药代动力学特性。然后，结构微调将为系统性炭疽感染患者提供一个临床候选方案，这些患者无法通过抗生素拯救。 -Pro-Vai-Leu-Pro-Ala-Leu-Thr- LF基板阶段2 和卵裂部位

DESCRIPTION (provided by applicant): Silanediols are novel transition-state analog protease inhibitors pioneered in the Principal Investigator's laboratory. These structures are effective inhibitors of metalloprotease enzymes at low nanomolar (nM) levels and can cross cell membranes at rates comparable to non-silane (commercial) pharmaceuticals. B. anthracis LF is a metalloprotease and the source of anthrax toxicity. No effective inhibitor of this enzyme has been described. The initial phase of this research will produce a silanediol inhibitor of LF using known substrate specificities. The second phase will structurally alter this inhibitor to remove the peptide character and thereby improve pharmacokinetic properties. Structural fine-tuning will then yield a clinical candidate for victims of systemic anthrax infection who cannot be saved by antibiotics. -Pro-VaI-Leu-Pro-Ala-Leu-Thr- LF substrate Phase 2 and site of cleavage