Mangel W F, McGrath W J, Brown M T, Baniecki M L, Barnard D L, Pang Y P
Biology Department, Brookhaven National Laboratory, Upton, NY 11973-5000, USA.
Curr Med Chem. 2001 Jul;8(8):933-9. doi: 10.2174/0929867013372742.
Combination therapy in the treatment of viral infections in which, for example, three different drugs against three different targets on three independent proteins are administered, has been highly successful clinically. However, it is only a matter of time before a virus will arise resistant to all three drugs, because the mutations leading to drug resistance are independent of each other. But, what if the mutations leading to drug resistance are not independent of each other, but confer some cost to the virus? If the cost is too great, than resistance may not arise. To impose such a cost in the clinical treatment of viral infections, we propose a new form of combination therapy. Here, three different drugs against three different targets on the same virus-coded protein are administered. If the physiological functions of the three different target sites are not independent of each other, then, a mutation at one site may alter the physiological functions at the other sites. We present a model system in which to test the efficacy of this new form of triple combination therapy. Human adenovirus has a virus-coded proteinase that is essential for the synthesis of infectious virus. It contains an active site and two cofactor binding sites; the functions of the active site are dependent upon the cofactors interacting with their binding sites. We describe how to obtain drugs against the three different sites.
联合疗法在治疗病毒感染方面已取得了巨大的临床成功，例如，针对三种独立蛋白质上的三个不同靶点使用三种不同的药物。然而，病毒对所有这三种药物产生耐药性只是时间问题，因为导致耐药性的突变是相互独立的。但是，如果导致耐药性的突变并非相互独立，而是给病毒带来某种代价呢？如果这种代价太大，那么耐药性可能就不会出现。为了在病毒感染的临床治疗中施加这样的代价，我们提出了一种新的联合疗法形式。在这里，针对同一病毒编码蛋白上的三个不同靶点使用三种不同的药物。如果这三个不同靶点位点的生理功能并非相互独立，那么一个位点的突变可能会改变其他位点的生理功能。我们提出了一个模型系统来测试这种新型三联联合疗法的疗效。人腺病毒有一种病毒编码蛋白酶，它对于感染性病毒的合成至关重要。它包含一个活性位点和两个辅因子结合位点；活性位点的功能依赖于与它们结合位点相互作用的辅因子。我们描述了如何获得针对这三个不同位点的药物。
