A hallmark of chemical biology is its ability to address biological challenges with chemical approaches derived from basic principles. Dan Kemp made seminal contributions toward this end. His research on the design and synthesis of molecular scaffolds laid an inspirational cornerstone for contemporary chemical biology. Daniel Schaeffer Kemp was born in Portland, Oregon and raised in Missoula, Montana. He returned to Portland to study chemistry at Reed College, where he performed research with Arthur F. Scott on the reactivity of divalent chromium. He was a National Science Foundation graduate fellow at Harvard University under the supervision of R. B. Woodward, doing research on the reactivity of the N-ethylbenzisoxazolium cation.(1,2) Following election to the Harvard Society of Fellows, Kemp joined the faculty of the Department of Chemistry at MIT. He was on the faculty there for over 40 years, supervising the doctoral research of 55 graduate students and mentoring dozens of postdoctorates and undergraduate students. Alumni from his laboratory have become renowned leaders in academia and industry. Here, we recount the impact of his research related to peptides and proteins. Modern methods of protein synthesis rely on the ligation of synthetic peptides. The intellectual underpinnings for this field were spawned in the Kemp laboratory. The basis was established in 1975, when Kemp showed that a carbinolamine could “capture” a proximal ester.(3,4) Throughout the 1980s, this concept evolved in the Kemp laboratory based on a key revelation: “Of the functional groups that appear in peptides, the thiol function of cysteine offers the greatest potential for meeting the...capture requirements.”(5) Kemp’s “prior thiol capture” method employed 4-hydroxy-6-mercaptodibenzofuran to enforce proximity between coupling partners (Figure 1). The strategy uses a thiol–disulfide exchange reaction in a capture step prior to an O→N acyl transfer reaction. Reduction of the disulfide bond yields the peptide product. Kemp and his research group demonstrated the utility of prior thiol capture in a variety of topical contexts.(6,7) Figure 1. Kemp’s prior thiol capture strategy for peptide ligation. With his prior thiol capture strategy, Kemp was the first to demonstrate the chemoselective ligation of unprotected peptide fragments. In addition, he was the first to use a transient covalent bond to facilitate the ligation of peptides. These two concepts are central to modern methods of protein synthesis. In the 1990s, Kemp’s work on peptides transitioned from their synthesis to their conformational control.(8) In groundbreaking work, he pioneered the use of scaffolds to stabilize the most abundant secondary structural elements in proteins: the α-helix and the β-sheet. Early on, Kemp recognized that the intrinsic constraints of proline could be useful in an α-helix template. Guided by meticulous models, he discovered that a properly placed thioether bridge constrains vicinal proline residues in an ideal conformation for helix nucleation (Figure 2A). His scaffold enabled him to estimate helix-propensity values for pendant amino acid residues.(9) Although other (e.g., protein-based) models for quantifying helical propensity have been described, Kemp’s work is rarefied in its not only providing data in isolated peptides (where protein packing does not influence helix stability) but also and more importantly employing a prenucleated helix, which allows for a measure of helix propagation apart from helix initiation. These early synthetic strategies provided the conceptual framework for helices constrained by either hydrogen-bond surrogates or “staples,” which have become a mainstay for antagonizing protein–protein interactions. Figure 2. Kemp’s synthetic scaffolds for stabilizing α-helices (A) and β-sheets (B). Likewise, Kemp developed a scaffold for a β-sheet. Again, he relied on models, here that would enable him to enforce the geometry of hydrogen bonding between β-strands. He identified 2,8-diaminoepindolidione as an optimal template (Figure 2B).(10) The contours of his design can be seen in contemporary efforts to inhibit amyloid aggregation with preorganized β-strand mimics. Finally, we note that the Kemp name is embedded within the vernacular of bioorganic chemistry. Foremost is “Kemp’s triacid” (Figure 3A).(11) The equilibrium between its two chair conformations provides educators with exemplary lessons on the steric strain of 1,3-diaxial interactions and A values (CH₃ > CO₂H). The enforced intimacy of its 1,3,5-cis-carboxy groups has enabled enlightening studies on the energetics of hydrogen bonding and the contribution of proximity to chemical reactivity. By elaboration of its triaxial carboxy groups, Kemp’s triacid has served as the linchpin for novel supramolecular structures and a template for the collagen triple helix and other trimeric architectures. Moreover, the “Kemp elimination”,(12,13) in which a benzisoxazole(1,2) isomerizes to a salicylonitrile (Figure 3B), is an oft-used model reaction for the development of novel enzymic and other catalysts. Figure 3. An eponymous compound and reaction. (A) Kemp’s triacid. (B) The Kemp elimination. The scientific achievements of Dan Kemp led to his receipt of an Arthur C. Cope Scholar Award and the Ralph F. Hirschmann Award in Peptide Chemistry from the American Chemical Society, along with many other accolades. He was also a masterful teacher of chemistry and was celebrated for his captivating lectures in both undergraduate and graduate classrooms. Together with Frank Vellaccio, he wrote an influential textbook and associated workbook that modernized organic chemistry pedagogy and included prescient chapters on “Amino Acids, Proteins, and Nucleotides” and “Sugars and Oligosaccharides.”(14) In May 2020, Dan Kemp became a victim of the COVID-19 pandemic. As both the founder of the fields of templated peptide ligation and nucleated helices and sheets and an inspirational mentor and educator, he left an extraordinary legacy to chemical biology. This article references 14 other publications.

中文翻译：

---

丹尼尔·肯普（Daniel S. Kemp）（1936–2020）：生物有机化学的先驱

化学生物学的一个标志就是它具有利用源自基本原理的化学方法应对生物学挑战的能力。为此，丹·肯普（Dan Kemp）做出了开创性的贡献。他对分子支架设计和合成的研究为当代化学生物学奠定了鼓舞人心的基石。丹尼尔·谢弗·肯普（Daniel Schaeffer Kemp）出生于俄勒冈州的波特兰，在蒙大拿州的米苏拉（Missoula）长大。他回到波特兰在里德学院（Reed College）学习化学，在那里他与亚瑟·斯科特（Arthur F. Scott）进行了有关二价铬反应性的研究。在RB伍德沃德（RB Woodward）的监督下，他是哈佛大学（National Science Foundation）的研究生，研究了N的反应性。-ethylbenzisoxazolium阳离子（1,2）继当选为院士的哈佛学会，坎普加入化学麻省理工学院系任教。他在该学院任职40多年，负责指导55名研究生的博士研究，并指导数十名博士后和本科生。他实验室的校友已经成为学术界和工业界的知名领导者。在这里，我们叙述了他有关肽和蛋白质研究的影响。蛋白质合成的现代方法依赖于合成肽的连接。肯普实验室产生了这一领域的知识基础。该基础建立于1975年，当时肯普（Kemp）表明甲醇胺可以“捕获”近端酯。（3,4）在整个1980年代，这一概念在肯普（Kemp）实验室基于一个重要启示得到了发展：“在出现在肽中的官能团中，半胱氨酸的硫醇功能提供了满足...捕获要求的最大潜力。”（5）肯普的“先硫醇捕获”方法采用了4-羟基-6-巯基二苯并呋喃来实现接近耦合伙伴之间（图1）。该策略在O→N酰基转移反应之前的捕获步骤中使用硫醇-二硫键交换反应。二硫键的还原产生肽产物。肯普和他的研究小组证明了在各种局部情况下先前硫醇捕获的效用。（6,7）图1.肯普针对肽连接的先前硫醇捕获策略。肯普凭借其先前的硫醇捕获策略，率先证明了未保护肽段的化学选择性连接。此外，他是第一个使用瞬时共价键促进肽段连接的人。这两个概念对于现代蛋白质合成方法至关重要。在1990年代，肯普（Kemp）对肽的研究从其合成过渡到其构象控制。（8）在开创性的工作中，他率先使用支架来稳定蛋白质中最丰富的二级结构元素：α-螺旋和β-折叠。早些时候，坎普（Kemp）认识到脯氨酸的内在限制可能在α-螺旋模板中有用。在细致的模型指导下，他发现正确放置的硫醚桥可将邻位脯氨酸残基限制在理想的构象中，以进行螺旋成核（图2A）。他的支架使他能够估算悬垂氨基酸残基的螺旋倾向值。（9）尽管其他（例如，已经描述了用于量化螺旋倾向的基于蛋白质的）模型，Kemp的工作非常稀少，因为它不仅提供分离的肽中的数据（其中蛋白质的堆积不会影响螺旋的稳定性），而且更重要的是采用了预成核的螺旋，从而可以除螺旋引发外，螺旋传播的量度。这些早期的合成策略为受氢键替代物或“订书钉”限制的螺旋结构提供了概念框架，这些螺旋结构已成为拮抗蛋白质与蛋白质相互作用的主体。图2.用于稳定α-螺旋（A）和β-折叠（B）的肯普合成支架。同样，Kemp开发了一种用于β-折叠的支架。再次，他依靠模型，这将使​​他能够加强β链之间氢键的几何形状。他确定了2 8-diaminoepindolidione作为最佳模板（图2B）。（10）他的设计轮廓可以在当代通过预组织的β链模拟物抑制淀粉样蛋白聚集的努力中看到。最后，我们注意到，坎普（Kemp）名称已嵌入生物有机化学的本土语言中。最重要的是“肯普三酸”（图3A）。（11）两种椅子构型之间的平衡为教育工作者提供了有关1,3-双轴相互作用的空间应变和A值（CH ₃ > CO ₂ H）。1,3,5-顺式的强制亲密关系-羧基已使人们对氢键的能量学及其对化学反应性的贡献有启发性的研究成为可能。通过详细说明其三轴羧基，肯普氏三酸已成为新型超分子结构的关键，并成为胶原三螺旋和其他三聚体结构的模板。此外，苯并异恶唑（1,2）异构化为水杨腈的“肯普消除”（12,13）（图3B）是开发新型酶催化剂和其他催化剂的常用模型反应。图3.同义化合物和反应。（A）坎普的三酸。（B）消除坎普。丹·肯普（Dan Kemp）的科学成就使他获得了来自美国化学学会的肽化学方面的亚瑟·C·科普学者奖和拉尔夫·赫希曼奖，以及许多其他荣誉。他还是化学方面的高超老师，并因其在本科生和研究生课堂上的精彩演讲而闻名。他与弗兰克·韦拉西乔（Frank Vellaccio）一起撰写了有影响力的教科书和相关工作簿，对有机化学教育进行了现代化改造，并包括有关“氨基酸，蛋白质和核苷酸”和“糖和寡糖”的先见之明的章节。（14）2020年5月，丹·坎普成为COVID-19大流行的受害者。作为模板化肽连接领域和有核螺旋和片层领域的创始人，以及鼓舞人心的导师和教育家，他为化学生物学留下了非凡的遗产。本文引用了其他14个出版物。他还是化学方面的高超老师，并因其在本科生和研究生课堂上的精彩演讲而闻名。他与弗兰克·韦拉西乔（Frank Vellaccio）一起撰写了有影响力的教科书和相关工作簿，对有机化学教育进行了现代化改造，并包括有关“氨基酸，蛋白质和核苷酸”和“糖和寡糖”的先见之明的章节。（14）2020年5月，丹·坎普成为COVID-19大流行的受害者。作为模板化肽连接领域和有核螺旋和片层领域的创始人，以及鼓舞人心的导师和教育家，他为化学生物学留下了非凡的遗产。本文引用了其他14个出版物。他还是化学方面的高超老师，并因其在本科生和研究生课堂上的精彩演讲而闻名。他与弗兰克·韦拉西乔（Frank Vellaccio）一起撰写了有影响力的教科书和相关工作簿，对有机化学教育进行了现代化改造，并包括有关“氨基酸，蛋白质和核苷酸”和“糖和寡糖”的先见之明的章节。（14）2020年5月，丹·坎普成为COVID-19大流行的受害者。作为模板化肽连接领域和有核螺旋和片层领域的创始人，以及鼓舞人心的导师和教育家，他为化学生物学留下了非凡的遗产。本文引用了其他14个出版物。他撰写了一份颇有影响力的教科书和相关工作簿，对有机化学教学进行了现代化改造，并包括有关“氨基酸，蛋白质和核苷酸”和“糖和寡糖”的先见之明的章节。（14）2020年5月，Dan Kemp成为COVID-的受害者19大流行。作为模板化肽连接领域和有核螺旋和片层领域的创始人，以及鼓舞人心的导师和教育家，他为化学生物学留下了非凡的遗产。本文引用了其他14个出版物。他撰写了一份颇有影响力的教科书和相关工作簿，对有机化学教学进行了现代化改造，并包括有关“氨基酸，蛋白质和核苷酸”和“糖和寡糖”的先见之明的章节。（14）2020年5月，Dan Kemp成为COVID-的受害者19大流行。作为模板化肽连接领域和有核螺旋和片层领域的创始人，以及鼓舞人心的导师和教育家，他为化学生物学留下了非凡的遗产。本文引用了其他14个出版物。