Studies in Bioorganic Chemistry and Chemical Biology - Investigating Fundamentals for Lead Applications

我实验室的学员将化学反应的基本原理应用于生物分子，如多肽、寡核苷酸、杂环、脱氧核酶和硼酸盐，作为生物学中的探针和试剂。我们在化学和生物学的这四个不同的领域发表了竞争性的文章。 我实验室的学员i)掌握杂原子功能化方面的先进合成方法，ii)发展机械物理有机化学方面的关键能力，iii)应用生物偶联、分子生物学和组合选择技术。凭借这些独特的技能，学员在化学和生物学的界面上提出各种问题，在那里他们合成具有新颖和令人兴奋的特性的新化学实体，这些新的化学实体将创造新的知识，同时解决生物技术和医学中测试与生物过程相关的机械假说的副产品和应用。在过去的5年里，我们在备受赞誉的同行评议的期刊上发表了以下工作：1)合成DNAzyme，2)硼酸的物理-有机研究，3)多肽毒素的化学生物学，以及4)DNA启发的“Janus”杂环的合成，用于序列特异性DNA识别。 我们在我的实验室中研究的主要问题如下： 1)合成配体对DNA的序列特异性识别是控制特定基因表达和研究细胞内DNA结构、功能和可及性的重要目标。随着对识别互补DNA碱基对的Janus-AT/GC核苷的研究，还提出了新的杂环化合物。 2)环肽的研究，其中二硫键被取代以生成新的具有生物活性的氧化还原惰性多肽。关于Amanitin和Poloidin的拟议工作，掌握了天然产品毒素识别蛋白质折叠的基本方面的线索。通过这些毒素的合成，我们已经在另外两个生物活性多肽中发现了新的生物活性，它们是镇痛剂和生长抑制剂。 3)化学修饰的基于DNA的催化剂和适配子：核酸是一个令人兴奋的技术平台，用于选择能够在医学和化学上进行重要转化的催化剂和配体，特别是在包含蛋白质类功能的新型杂化DNA催化剂方面。这些催化剂对RNA的切割和传感都很有用。 4)生物学中的有机硼酸盐：我们进行了各种硼酸盐的基础研究，用于与亲电体和亲核剂反应，用于原反应和氧化脱碳反应。这项工作的一个主要应用是18F-PET成像，它代表了临床前/临床成像的一种选择成像方式。我们感兴趣的是C-B和B-F键形成的基础应用于新的生物探针和C-F键形成的方法。

Trainees in my lab apply fundamental principles of chemical reactivity to biological molecules such as peptides, oligonucleotides, heterocycles, DNAzymes, and boronates as probes and reagents in biology. We have published competitively in these four disparate areas at the interface of chemistry and biology. Trainees in my lab i) master aspects of advanced synthetic methods in heteroatom functionalization, ii) develop critical abilities in mechanistic physical organic chemistry, and iii) apply techniques in bioconjugation, molecular biology and combinatorial selection. With these unique skills, trainees attack diverse questions at the interface of chemistry and biology where they synthesize new chemical entities with novel and exciting properties that will create new knowledge while addressing spin-off applications in biotechnology and medicine that test mechanistic hypotheses related to biological processes. Over the past 5 years, we have published work in highly regarded, peer-reviewed journals on: 1) synthetic DNAzymes, 2) physical-organic studies of boronic acids 3) chemical biology of peptide toxins, and 4) synthesis of DNA-inspired “Janus”-heterocycles for the application of sequence-specific DNA recognition. The major questions we are pursuing in my lab are the following: 1) Sequence specific recognition of DNA by synthetic ligands represents an important goal for controlling specific gene expression and investigating DNA structure, function, and accessibility inside cells. New heterocycles are also proposed along with ongoing investigations of Janus-AT/GC nucleosides that recognize a complementary DNA base pair. 2) Investigation of cyclic peptides where the disulfide bond is replaced to create new biologically active redox-inert peptides. Proposed work on amanitin and phalloidin, hold clues as to fundamental aspects of protein-fold recognition by natural product toxins. Through the synthesis of these toxins, we have identified new bioactivity in two other bioactive peptides as analgesics and growth suppressors. 3) Chemically Modified DNA-based catalysts and aptamers: Nucleic acids represent an exciting technological platform for selecting catalysts and ligands that are capable of medicinally and chemically important transformations, particularly in terms of novel hybrid DNA catalysts that contain protein-like functionalities. These catalysts are useful for RNA cleavage and for sensing. 4) Organoboronates in biology: We have undertaken fundamental studies of various boronates for reaction with electrophiles and nucleophiles for proto and oxidative deboronation. A major application of this work is 18F-PET imaging which represents a choice imaging modality for preclinical/clinical imaging. We are interested in the fundamental applications of C-B and B-F bond formation for new bioprobes and methods for C-F bond formation.