Anticancer peptide therapeutics

尽管几十年来制药公司的研发(R&D)支出呈指数级增长 行业内，FDA平均每年批准的新药数量为25种左右，一直停滞不前。这个 研发支出失控的不可持续趋势直接导致了全球医疗保健成本的飙升 他强调，迫切需要新的毒品目标和药物类别。蛋白质-蛋白质相互作用(PPI)控制所有 细胞过程的方方面面，被认为是药物发现和最终药物靶点的“圣杯” 疾病干预。不幸的是，现有的两大类药物--低分子化合物 抗体在干扰细胞内PPI方面是有效的。另一方面，尽管小肽能够 在有效干扰PPI方面，它们通常缺乏类似药物的性质，这主要是因为它们对蛋白质分解的敏感性 体内降解。解决药物发现中这个长期谜团的一个明智的办法是侧链装订的L肽 和抗蛋白水解性D-多肽。拮抗MDM2/MDMX激活P53是最有希望的方法之一 抗癌治疗的治疗范例。我们最近开发了一系列高亲和力的L和D-肽 MDM2拮抗剂有效抑制P53和MDM2依赖的体内外肿瘤生长 举止。然而，为了实现持续和强劲的P53激活和最佳治疗效果，双特异性 需要MDM2和MDMX的拮抗剂。这项拟议研究的总体目标是开发超高分辨率的 MDM2和MDMX的亲和力、双特异性和抗蛋白水解性多肽拮抗剂作为一种强大的P53- TP53基因罕见突变的急性髓系白血病和MDM2的激活治疗 和MDMX经常被扩增或过度表达。该项目可能会导致在现有武器的基础上增加新的武器 抗癌武器库和广泛影响许多靶向分子治疗的多肽疗法的发展 其他疾病也是如此。

Despite an exponential increase over decades in research and development (R&D) expenditures by the pharmaceutical industry, the average number of new drugs approved annually by the FDA, 25 or so, has remained stagnant. The unsustainable trend of runaway spending in R&D directly contributes to skyrocketing health care costs across the country, underscoring an urgent need for new drug targets and classes. Protein-protein interactions (PPIs) control all aspects of cellular processes and are considered to be the “Holy Grail” in drug discovery and ultimate drug targets for disease intervention. Unfortunately, neither of the two major classes of existing drugs – low molecular weight compounds and antibodies are effective in interfering with intracellular PPIs. On the other hand, although small peptides are capable of effectively disrupting PPIs, they generally lack drug-like properties due primarily to their susceptibility to proteolytic degradation in vivo. A sensible solution to this long-running enigma in drug discovery is side chain-stapled L-peptides and proteolysis-resistant D-peptides. Antagonizing MDM2/MDMX to activate p53 is one of the most promising therapeutic paradigms for anticancer therapy. We have recently developed a series of high-affinity L- and D-peptide antagonists of MDM2 that effectively suppress tumor growth in vitro and in vivo in a p53- and MDM2-dependent manner. To achieve sustained and robust p53 activation and optimal therapeutic efficacy, however, dual-specificity antagonists of both MDM2 and MDMX are needed. The overall goal of this proposed research is to develop ultrahigh- affinity, dual-specificity, and proteolysis-resistant peptide antagonists of MDM2 and MDMX as a powerful p53- activating modality for the treatment of acute myeloid leukemia – where mutations of the TP53 gene are rare and MDM2 and MDMX are often amplified or over-expressed. This project may lead to the addition of new weapons to the existing anticancer arsenal and broadly impact the development of peptide therapeutics for targeted molecular therapy of many other diseases as well.