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

生物有机化学和化学生物学研究 - 研究先导应用的基础知识

• 批准号: RGPIN-2015-06534
• 负责人: Perrin, David
• 金额: $ 6.48万
• 依托单位: University of British Columbia
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=692381
• 关键词: Studies; Bioorganic; Chemistry; Chemical; Biology

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. **

我实验室的实习生将化学反应的基本原理应用于生物分子，如肽，寡核苷酸，杂环，DNA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界面上在这四个不同的领域发表了竞争性文章。我实验室的学员i）掌握杂原子官能化的先进合成方法的各个方面，ii）发展机械物理有机化学的关键能力，iii）应用生物共轭，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解决各种问题，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，这些特性将创造新的知识，同时解决生物技术和医学中的副产品应用，测试与生物过程相关的机械假说。在过去的5年里，我们在高度重视的同行评审期刊上发表了以下工作：1）合成DNA酶，2）硼酸的物理有机研究3）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识别的应用。我们在我的实验室追求的主要问题如下：******1）合成配体对DNA的序列特异性识别代表了控制特定基因表达和研究DNA结构，功能和细胞内可及性的重要目标。 新的杂环也被提出沿着正在进行的Janus-AT/GC核苷的研究，它识别互补的DNA碱基对。* 2)二硫键被取代以产生新的生物活性氧化还原惰性肽的环肽的研究。鹅膏蕈碱和鬼笔环肽的拟议工作，持有天然产物毒素蛋白质折叠识别的基本方面的线索。通过这些毒素的合成，我们已经确定了另外两种生物活性肽作为镇痛剂和生长抑制剂的新生物活性。3)基于化学修饰的DNA的催化剂和适体：核酸代表了一个令人兴奋的技术平台，用于选择能够进行医学和化学重要转化的催化剂和配体，特别是在含有蛋白质样功能的新型混合DNA催化剂方面。 这些催化剂可用于RNA切割和传感。**4）生物学中的有机硼酸盐：我们已经进行了各种硼酸盐与亲电试剂和亲核试剂反应的基础研究，用于质子和氧化脱硼。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键形成的新的生物探针和C-F键形成的方法的基本应用。**