From Total Synthesis-Inspired Methodology to Anti-HIV therapy

有机化学在原子、分子及其反应的物理世界和生物科学之间架起了一座桥梁，其中一个特别重要的领域是新药的开发。许多药物最初的灵感来自于自然经过数百万年提炼的天然产品/分子，它们可以对人类疾病具有强大的、特定的生物活性。因此，天然产物代表着药物研究的高度起点；然而，它们作为药物先导的发展可能会因天然丰度较低而受阻。一种解决方案(避免自然栖息地的毁灭)是人工制备，即天然产物的“完全合成”。从历史上看，这一过程可能需要数年时间，这一时间尺度无法满足自动药物筛选的要求。然而，应用改进的、有效的化学方法，使这些天然药物(以及具有更高疗效的非天然“类似物”)能够快速和可扩展地合成，现在是有机化学家能够掌握的一个目标。因此，天然产品化学即将被制药界重新接受；这一提议旨在表明，天然产品目标本身只是有机化学家所能提供的东西的开始。传统上，有机化学可以分为两个研究流派。新反应的发展是提高化学合成效率的基础，它探索了在原子之间形成键的新方法。通常没有具体的目标，研究人员可以求助于大量的天然产品，以寻找一种展示他们的方法的产品。相比之下，在结构上具有挑战性的分子的全合成领域(这为方法学提供了最终的测试基础)，化学家们倾向于使用已知的方法来打造他们能够到达给定目标的最有效的路径。合成本身的挑战通常要求选择的反应是有先例和可靠性的。这一建议试图颠倒这一公认的反应发展顺序：天然产物被视为新反应的灵感来源，而不是任意设置。生物上重要的目标将被选择，并为发明一种有效和吸引人的合成转化提供动力。在一般情况下发展之后，这一方法将在其原意/天然产物和类似物的完全合成的背景下应用。提出了两个项目，证明了天然产物有潜力启动有用的、具有广泛适用性的一般反应的开发：西帕星A是一种包含有趣的不饱和基序的有效抗生素，它是手性联烯合成的灵感来源。蓝果内酯G和红花内酯A具有抗艾滋病毒的特性，是合成双环或三环分子的创新路线的基础。我的提案还详细介绍了一个合作项目，旨在寻找抑制艾滋病毒的新方法。艾滋病毒生命周期中一个目前未被研究的领域是将病毒RNA‘包装’成新的病毒颗粒。包装是通过将病毒蛋白Gag与病毒RNA中称为psi的区域结合来启动的。众所周知，psi和一个截短的类似物，被含有带有亲核侧链的氨基酸的GAG区域特异性结合。我们打算设计包含一个亲电位点的PSI类似物，它将结合到GAG上，并将该位点放置在亲核侧链氨基酸附近，导致形成共价键，不可逆结合GAG，并抑制包装。这是一个令人兴奋和未被探索的化学生物学领域，它利用了有机化学家和病毒学家的专业知识，并可能对其他病毒特异性RNA-蛋白质相互作用的抑制剂的设计产生影响。

Organic chemistry provides a bridge between the physical world of atoms, molecules and their reactions, and the biological sciences, with one area of particular importance being the development of new medicines. Many drugs are originally inspired by 'natural products' / molecules refined by Nature over millions of years, which can have potent, specific biological activity against human diseases. As such, natural products represent highly advanced starting points for pharmaceutical research; however, their development as drug leads can be hampered by low natural abundance. One solution (which avoids decimation of the natural habitat) is the artificial preparation, or 'total synthesis' of the natural product. Historically, this process can take many years, a timescale which cannot satisfy the requirements of automated pharmaceutical screening. However, the application of improved, efficient chemical methods which enable rapid and scalable syntheses of these natural medicines (and non-natural 'analogues' with improved efficacy), is now an aim that is within the grasp of the organic chemist. Natural products chemistry thus stands on the brink of being re-embraced by the pharmaceutical community; this proposal aims to show that the natural product target itself is just the beginning of what an organic chemist can deliver.Traditionally, organic chemistry can be divided into two schools of research. The development of new reactions, which is fundamental to improving the efficiency of chemical synthesis, investigates new ways to form bonds between atoms. Often there is no specific target, and researchers can resort to scouring a vast array of natural products for one which will showcase their methodology. By contrast, in the field of total synthesis of structurally challenging molecules (which provides the ultimate testing ground for methodology), chemists tend to use known methods to forge the most efficient path they are able to a given target. The challenge of synthesis itself usually dictates that the choice of reaction is one with precedent and reliability.This proposal seeks to reverse this accepted order of reaction development: Natural products are seen as the inspiration for new reactions, rather than an arbitrary setting. Biologically important targets will be selected, and provide the impetus for the invention of an efficient and appealing synthetic transformation. Following development in a general setting, this method will then be applied in the context it was intended / a total synthesis of the natural product and analogues. Two projects which demonstrate the potential for natural products to initiate the development of useful, general reactions with broad applicability are proposed: Cepacin A, a potent antibiotic which contains an intriguing unsaturation motif, is the inspiration for a novel synthesis of chiral allenes. Lancifodilactone G and rubriflordilactone A, which possess anti-HIV properties, are the basis for an innovative route to bi- or tricyclic molecules.My proposal also details a collaborative project towards new methods for HIV inhibition. A currently uninvestigated area of the HIV life cycle is the 'packaging' of viral RNA into new virus particles. Packaging is initiated by binding of the viral protein Gag to a region of the viral RNA called psi. It is known that psi, and a truncated analogue, are bound specifically by a region of Gag that contains amino acids with nucleophilic sidechains. We intend to design psi analogues containing an electrophilic site, which will bind to Gag and place this site in proximity to the nucleophilic sidechain amino acids, leading to the formation of a covalent bond, irreversible binding of Gag, and inhibition of packaging. This is an exciting and unexplored area of chemical biology which harnesses the expertise of both the organic chemist and the virologist, and could have implications for the design of inhibitors for other virus specific RNA-protein interactions.