Pub Date : 2022-01-01DOI: 10.1021/bk-2022-1417.ch007
Dehua Pei
Intracellular protein-protein interactions (PPIs) represent a large class of exciting as well as challenging drug targets for traditional drug modalities (i.e., small molecules and biologics). Peptides (especially cyclic peptides) have proven highly effective as PPI inhibitors in vitro but are generally impermeable to the cell membrane. The recent discovery of a family of highly active cyclic cell-penetrating peptides (CPPs) has enabled the delivery of peptides into the cytosol of mammalian cells at therapeutically relevant levels. This chapter describes the various strategies that have been developed to conjugate or integrate different types of peptidyl cargoes (e.g., linear, cyclic, and stapled peptides) with cyclic CPPs to generate cell-permeable, metabolically stable, and biologically active macrocyclic peptides against intracellular targets including PPIs.
{"title":"Designing Cell-Permeable Peptide Therapeutics That Enter the Cell by Endocytosis.","authors":"Dehua Pei","doi":"10.1021/bk-2022-1417.ch007","DOIUrl":"https://doi.org/10.1021/bk-2022-1417.ch007","url":null,"abstract":"<p><p>Intracellular protein-protein interactions (PPIs) represent a large class of exciting as well as challenging drug targets for traditional drug modalities (i.e., small molecules and biologics). Peptides (especially cyclic peptides) have proven highly effective as PPI inhibitors in vitro but are generally impermeable to the cell membrane. The recent discovery of a family of highly active cyclic cell-penetrating peptides (CPPs) has enabled the delivery of peptides into the cytosol of mammalian cells at therapeutically relevant levels. This chapter describes the various strategies that have been developed to conjugate or integrate different types of peptidyl cargoes (e.g., linear, cyclic, and stapled peptides) with cyclic CPPs to generate cell-permeable, metabolically stable, and biologically active macrocyclic peptides against intracellular targets including PPIs.</p>","PeriodicalId":72050,"journal":{"name":"ACS symposium series. American Chemical Society","volume":"1417 ","pages":"179-197"},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10448808/pdf/nihms-1870899.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10103677","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-01-01Epub Date: 2019-07-12DOI: 10.1021/bk-2019-1317.ch004
Atanu Banerjee, Jia Li, Monika A Molenda, William W Brennessel, Ferman A Chavez
We report the characterization of [Fe(T1Et4iPrIP)(sal)] (2) (T1Et4iPrIP = tris(1-ethyl-4-isopropyl-imidazolyl)phosphine; sal2- = salicylate dianion), which serves as a model for substrate-bound salicylate dioxygenase (SDO). Complex 2 crystallizes in the monoclinic space group P21/n with a = 10.7853(12) Å, b = 16.5060(19) Å, c = 21.217(2) Å, β = 94.489(2)°, and V = 3765.5(7) Å3. The structure consists of FeII bonded in distorted square pyramidal geometry (τ = 0.32) with two salicylate oxygens and two T1Et4iPrIP nitrogens serving as the base and the apical position occupied by the other ligand nitrogen. [Fe(T1Et4iPrIP)(OTf)2] (1), the precursor for 2, catalyzes the cleavage of 1,4-dihydroxy-2-naphthoate in the presence of O2. Complex 1 is also capable of cleaving the salicylate aromatic ring in the presence of H2O2. The progression of this reaction toward product formation involves an FeIII-phenoxide species.
{"title":"A Biomimetic System for Studying Salicylate Dioxygenase.","authors":"Atanu Banerjee, Jia Li, Monika A Molenda, William W Brennessel, Ferman A Chavez","doi":"10.1021/bk-2019-1317.ch004","DOIUrl":"https://doi.org/10.1021/bk-2019-1317.ch004","url":null,"abstract":"<p><p>We report the characterization of [Fe(T1Et4iPrIP)(sal)] (<b>2</b>) (T1Et4iPrIP = tris(1-ethyl-4-isopropyl-imidazolyl)phosphine; sal<sup>2-</sup> = salicylate dianion), which serves as a model for substrate-bound salicylate dioxygenase (SDO). Complex <b>2</b> crystallizes in the monoclinic space group <i>P</i>2<sub>1</sub>/n with <i>a</i> = 10.7853(12) Å, <i>b</i> = 16.5060(19) Å, <i>c</i> = 21.217(2) Å, <i>β</i> = 94.489(2)°, and <i>V</i> = 3765.5(7) Å<sup>3</sup>. The structure consists of Fe<sup>II</sup> bonded in distorted square pyramidal geometry (<i>τ</i> = 0.32) with two salicylate oxygens and two T1Et4iPrIP nitrogens serving as the base and the apical position occupied by the other ligand nitrogen. [Fe(T1Et4iPrIP)(OTf)<sub>2</sub>] (<b>1</b>), the precursor for <b>2</b>, catalyzes the cleavage of 1,4-dihydroxy-2-naphthoate in the presence of O<sub>2</sub>. Complex <b>1</b> is also capable of cleaving the salicylate aromatic ring in the presence of H<sub>2</sub>O<sub>2</sub>. The progression of this reaction toward product formation involves an Fe<sup>III</sup>-phenoxide species.</p>","PeriodicalId":72050,"journal":{"name":"ACS symposium series. American Chemical Society","volume":"1317 4","pages":"71-83"},"PeriodicalIF":0.0,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1021/bk-2019-1317.ch004","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38883747","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2018-01-01DOI: 10.1021/BK-2018-1275.CH016
S. Hayes
Incorporating research into undergraduate curricula, especially at an early stage, has been linked to improved critical thinking, intellectual independence, and student retention. This results in a graduating population more ready to enter the workforce or graduate school. Similarly, mentoring has been linked to enhanced self-efficacy, persistence, and desire to pursue graduate studies. We have designed two linked courses that engage second-year undergraduate students in developing self-directed research projects, proposal writing. These courses also serve to nucleate relationships with graduate student mentors enrolled in the companion course. Early-career undergraduate students, with no previous research experience, receive formal training in the process of scientific research from a faculty process mentor while working with a graduate student content mentor to develop an independent research project and write a proposal and embed themselves in an active research group. Undergraduate students may elect to submit their proposals for funding to continue the project, either as part of the upper division research course required for graduation or independently. Graduate students enrolled in the companion course gain experience in mentoring through formal training and actively mentoring early-career undergraduates. This chapter presents both the model and early assessment of our integrated approach to engaging early career undergraduates in developing and funding independent research projects with the support of empowering mentoring relationships.
{"title":"Engaging Early-Career Students in Research Using a Tiered Mentoring Model.","authors":"S. Hayes","doi":"10.1021/BK-2018-1275.CH016","DOIUrl":"https://doi.org/10.1021/BK-2018-1275.CH016","url":null,"abstract":"Incorporating research into undergraduate curricula, especially at an early stage, has been linked to improved critical thinking, intellectual independence, and student retention. This results in a graduating population more ready to enter the workforce or graduate school. Similarly, mentoring has been linked to enhanced self-efficacy, persistence, and desire to pursue graduate studies. We have designed two linked courses that engage second-year undergraduate students in developing self-directed research projects, proposal writing. These courses also serve to nucleate relationships with graduate student mentors enrolled in the companion course. Early-career undergraduate students, with no previous research experience, receive formal training in the process of scientific research from a faculty process mentor while working with a graduate student content mentor to develop an independent research project and write a proposal and embed themselves in an active research group. Undergraduate students may elect to submit their proposals for funding to continue the project, either as part of the upper division research course required for graduation or independently. Graduate students enrolled in the companion course gain experience in mentoring through formal training and actively mentoring early-career undergraduates. This chapter presents both the model and early assessment of our integrated approach to engaging early career undergraduates in developing and funding independent research projects with the support of empowering mentoring relationships.","PeriodicalId":72050,"journal":{"name":"ACS symposium series. American Chemical Society","volume":"28 1","pages":"273-289"},"PeriodicalIF":0.0,"publicationDate":"2018-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82694989","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2018-01-01DOI: 10.1021/BK-2018-1276.CH001
J. Guerard, S. Hayes
In this chapter, we present a model for an entry-level lab-based undergraduate environmental chemistry course delivered simultaneously by face-to-face and distance modalities. This course frames conceptual chemistry using the theme of Alaskan Arctic environmental issues in order to increase engagement and perceived relevance of chemical principles. Synchronously delivered lectures and guided discussions along with the incorporation of peer-mentored research projects encourage the development of a learning community among students in the course. Distance students participate in the same virtual and "kitchen" lab experiments as on-campus students, thus providing an educationally equivalent curriculum to all. In mixed teams of on-campus and distance students, all students participate in research projects to allow entry-level students to explore their interests in STEM fields. Students thereby begin to build an identity as a scientist and hopefully this course will serve as a mechanism to improve recruitment and retention of students, especially from traditionally underrepresented groups, in the chemical sciences and other STEM fields of study. Responses from the first course offering communicated positive attitudes toward the course content and methods.
{"title":"Introduction to Environmental Chemistry of the Arctic: An Introductory, Lab-Based Course Offered Both Face-to-Face and by Distance.","authors":"J. Guerard, S. Hayes","doi":"10.1021/BK-2018-1276.CH001","DOIUrl":"https://doi.org/10.1021/BK-2018-1276.CH001","url":null,"abstract":"In this chapter, we present a model for an entry-level lab-based undergraduate environmental chemistry course delivered simultaneously by face-to-face and distance modalities. This course frames conceptual chemistry using the theme of Alaskan Arctic environmental issues in order to increase engagement and perceived relevance of chemical principles. Synchronously delivered lectures and guided discussions along with the incorporation of peer-mentored research projects encourage the development of a learning community among students in the course. Distance students participate in the same virtual and \"kitchen\" lab experiments as on-campus students, thus providing an educationally equivalent curriculum to all. In mixed teams of on-campus and distance students, all students participate in research projects to allow entry-level students to explore their interests in STEM fields. Students thereby begin to build an identity as a scientist and hopefully this course will serve as a mechanism to improve recruitment and retention of students, especially from traditionally underrepresented groups, in the chemical sciences and other STEM fields of study. Responses from the first course offering communicated positive attitudes toward the course content and methods.","PeriodicalId":72050,"journal":{"name":"ACS symposium series. American Chemical Society","volume":"30 1","pages":"1-19"},"PeriodicalIF":0.0,"publicationDate":"2018-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77185442","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2009-12-20DOI: 10.1021/bk-2009-1025.ch008
Cynthia J Burrows
As a consequence of life's coexistence with the reactive diradical O(2), cells have adapted biochemical defense mechanisms for protection from oxidative damage. Nevertheless, it is estimated that each cell's genomic DNA undergoes thousands of oxidative hits per day, and even more under conditions of stress. Unrepaired oxidative damage to DNA leads to mutations that underlie cancer, aging and neurological disease. Recent studies have helped unravel the oxidation chemistry of the DNA bases, and the myriad biochemical responses of DNA processing enzymes that battle against mutation. On the positive side, oxidative damage to nucleobases may accelerate the evolution of genomes and could have played a role in the ancestry of redox-active nucleoside cofactors as well as the adaptation of early life to changes in the environment.
{"title":"Surviving an Oxygen Atmosphere: DNA Damage and Repair.","authors":"Cynthia J Burrows","doi":"10.1021/bk-2009-1025.ch008","DOIUrl":"https://doi.org/10.1021/bk-2009-1025.ch008","url":null,"abstract":"<p><p>As a consequence of life's coexistence with the reactive diradical O(2), cells have adapted biochemical defense mechanisms for protection from oxidative damage. Nevertheless, it is estimated that each cell's genomic DNA undergoes thousands of oxidative hits per day, and even more under conditions of stress. Unrepaired oxidative damage to DNA leads to mutations that underlie cancer, aging and neurological disease. Recent studies have helped unravel the oxidation chemistry of the DNA bases, and the myriad biochemical responses of DNA processing enzymes that battle against mutation. On the positive side, oxidative damage to nucleobases may accelerate the evolution of genomes and could have played a role in the ancestry of redox-active nucleoside cofactors as well as the adaptation of early life to changes in the environment.</p>","PeriodicalId":72050,"journal":{"name":"ACS symposium series. American Chemical Society","volume":"2009 ","pages":"147-156"},"PeriodicalIF":0.0,"publicationDate":"2009-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1021/bk-2009-1025.ch008","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"28976406","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
We report the application of diphenyloxazinone glycinate chiral templates to asymmetric syntheses of cylindrospermospin, 7-epi-cylindrospermopsin, 7-deoxycylindrospermopsin, and spirotryprostatins A and B. Synthetic studies toward quinine, nakadomarin A, and palau'amine using these templates are also described.
我们报告了二苯基噁嗪酮甘氨酸手性模板在不对称合成圆柱精蛋白、7-表环状吲哚精蛋白、7-脱氧环状吲哚精蛋白、螺螺芪 A 和 B 中的应用。
{"title":"New Tricks in Amino Acid Synthesis: Applications to Complex Natural Products.","authors":"Robert M Williams, Cameron M Burnett","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>We report the application of diphenyloxazinone glycinate chiral templates to asymmetric syntheses of cylindrospermospin, 7-epi-cylindrospermopsin, 7-deoxycylindrospermopsin, and spirotryprostatins A and B. Synthetic studies toward quinine, nakadomarin A, and palau'amine using these templates are also described.</p>","PeriodicalId":72050,"journal":{"name":"ACS symposium series. American Chemical Society","volume":"1009 ","pages":"420-442"},"PeriodicalIF":0.0,"publicationDate":"2009-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2886987/pdf/nihms178104.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"29068828","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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