DOCSLIB.ORG

Addressing Delivery and Synthesis Challenges for Peptide-Based Cancer Vaccines

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Addressing Delivery and Synthesis Challenges for Peptide-Based Cancer Vaccines Addressing delivery and synthesis challenges for peptide-based cancer vaccines By Rebecca Lynn Holden B.S. Chemistry Baylor University, 2015 Submitted to the Department of Chemistry in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy in Chemistry at the Massachusetts Institute of Technology September 2020 © 2020 Massachusetts Institute of Technology All rights reserved Signature of Author: ________________________________________________ Department of Chemistry July 20, 2020 Certified by: ______________________________________________________ Bradley L. Pentelute Associate Professor of Chemistry Thesis Supervisor Accepted by: _____________________________________________________ Adam Willard Associate Professor Graduate Officer 1 2 This doctoral thesis has been examined by a committee of the Department of Chemistry as follows: Professor Elizabeth M. Nolan …………………………………………………………………. Thesis Committee Chair Ivan R. Cottrell Professor of Immunology Professor Bradley L. Pentelute………………………………………………………………….. Thesis Supervisor Associate Professor of Chemistry Catherine L. Drennan…………………………………………………………………………… Thesis Committee Member Professor of Biology and Chemistry, HHMI Investigator 3 4 Addressing delivery and synthesis challenges for peptide-based cancer vaccines By Rebecca Lynn Holden Submitted to the Department of Chemistry on July 20, 2020 in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy in Chemistry Abstract Therapeutic peptide vaccines have the potential to elicit and direct an anti-cancer T cell response, but their clinical efficacy has been limited in part by poor delivery to the lymphatic system, inefficient cell uptake, and scalable synthesis in the case of personalized vaccines. The work presented in this thesis explores several approaches to address these challenges. First, we use our fast-flow automated synthesis technology to confront the synthesis bottleneck for patient-specific ‘neoantigen’ vaccines, which have shown early promise but are hindered by slow production. We synthesize a particularly challenging set of peptides from a previous clinical trial as a test case, demonstrating that our technology can produce the majority of sequences in sufficient quantities with comparable or higher purity than a commercial vendor in a fraction of the time. Turning towards vaccine design, we explore several approaches to address the lymphatic and intracellular delivery of peptide antigens. We demonstrate the generality and anti-tumor efficacy of vaccines containing cell-penetrating peptides (CPPs), sequences shown to enhance the cell uptake of various cargo. We characterize their mechanism and identify several unanticipated contributors, namely trafficking to the lymph nodes, serum stability, and extended presentation in vivo. We then expand on an existing approach to mediate lymphatic trafficking via binding serum albumin by exploring additional albumin binding moieties. Next, we develop a straightforward and general approach to directly quantify antigen presentation and implement this technique to explore two strategies to design more effective vaccines, including CPPs. Finally, we build on previous work using CPPs to deliver antisense oligonucleotides (ASOs), another application that we pursued in tandem with cancer vaccines. We combine amphipathic and cationic CPPs to create chimeric sequences that synergistically enhance activity of an ASO and access new routes of uptake not utilized by either parent CPP. Drawing from our experience using CPPs to deliver ASOs as well as our expertise in peptide synthesis and design, we provide insight into the rapid production of personalized vaccines and efficient delivery of vaccine antigens. This thesis represents a new area of research for our lab, one in which we will hopefully continue to apply our unique skillset and perspective. Thesis Supervisor: Bradley L. Pentelute Associate Professor of Chemistry 5 Acknowledgements The past five years have been some of the greatest years of my life but also the hardest, challenging me in ways that I could not predict. Earning a PhD is a difficult journey; and earning a PhD while coming out is a real trip. I have learned so much, grown stronger as a person, and become a better and more confident scientist. I owe a great deal of gratitude to everyone who has helped me make it through. I want to start by thanking my thesis advisor, Prof. Brad Pentelute. His enthusiasm from the moment I joined the lab set the tone for my entire grad school career. I am grateful for his guidance and mentorship, which always seemed to be exactly what I needed. He encouraged me to propose my own ideas early on and his confidence in me allowed me to grow as an independent scientist. At the same time, he provided direction and encouragement whenever I needed it. His support extended beyond scientific guidance, helping me improve my communication and presentation skills and providing invaluable professional advice. Finally, of course, I would like to thank Brad for cultivating a supportive and collaborative lab culture that has significantly shaped both my research and my entire experience at MIT. I could not have asked for a more invested and supportive thesis committee chair than Prof. Liz Nolan. I want to thank her for being an amazing mentor. It was always evident during our meetings that she genuinely cared about my research and my growth as a scientist. I appreciate her many insightful questions and thoughtful suggestions over the years. I am especially grateful more recently for her postdoc application and general career advice. Than you to Prof. Cathy Drennan, who has been another incredible mentor. I appreciated her encouragement throughout grad school, particularly during my second- and third-year exams. Her advice for my postdoc search and her support with fellowship applications has been invaluable, and I am extremely grateful. I am thankful to my collaborators in the Irvine lab, beginning with Prof. Darrell Irvine, who has provided a great deal of advice and scientific guidance for many of the projects described in this thesis. I am also grateful to Coralie, whose insight and advice over the last few years helped me to be a better scientist and whose sincerity, thoughtfulness, and humor made her a great colleague and friend. Thank you to Kelly, who was both a collaborator and a mentor during my first couple of years in grad school. I am grateful for her organization and positivity getting several of these projects up and running. I would also like to thank Dan, Josetta, and Naveen for their contributions to our work. I would like to express my gratitude to Prof. Cathy Wu and Prof. Nir Hacohen for a productive and exciting collaboration on their neoantigen vaccines. I have learned a lot working with them and look forward to learning more in the future. I would also like to thank Keerthi, Sisi, Matt, Zhuting, and the whole Neovax subgroup. I cannot imagine what my experience in grad school would have been without my amazing colleagues and friends in the Pentelute lab. Thank you to my best friend Azin, whose compassion, vivacity, and sarcasm always brightened my day. I am grateful to have worked with someone so supportive, who was always willing to listen and help with anything going on in my research or personal life. Thank you to Nina, whose cheerfulness and style brightened our space. I am grateful for her thoughtfulness, generosity, and mentorship. I know I can turn to her any time in the future. I would like to thank Colin for being my first person in the lab and teaching me so much. He was a delight to work with and helped me through some of the hardest moments of grad school. Thank you to Justin for being an easygoing, practical, and encouraging friend and collaborator. I am grateful to Alex M. for being a willing teacher, a caring friend, and a fun roommate. He truly is the definition of precious. I would also like to thank Ethan for his commiseration and for the scientific input he happily provided anytime I asked. Thank you to Charlotte for being dependably upbeat and always willing to help. I owe a great deal of 6 gratitude to Anthony Q. for his tireless efforts to keep the Orbitrap running, as well as his down- to-earth kindness and his many, many, many jokes. I am thankful to Carly for being amazing to work with and a brilliant sand volleyball team captain. Thank you to Alex L. and Tuang for being my comrades throughout the grad school process, especially second- and third-year exams. I would like to thank Nick for being an enthusiastic collaborator and for organizing our immunotherapy super-group meetings. And finally, I would like to thank all of my other friends and colleagues who have made the past five years so enlightening and enjoyable: Katie, Jessie, Rachael, Zak, Mette, Diómedes, Joe, Aaron, Deborah, Surin, and everyone else in the Pentelute lab. I am also grateful to Christine, Katherine, and Alex (and Eli) from the Kiessling lab for their scientific input and friendship. I want to extend a huge thank you to all of the friends that I made outside of lab. In particular, I would like to thank Lindsey, who became an immediate friend and who has been a source of endless support, commiseration, and sangria. I also want to thank Marty, who was one of the first friends I made in Cambridge and whose kindness and originality have been welcome constants throughout grad school. I enjoyed our trips together almost as much as I enjoyed being roommates. Thank you to Sheena, the gentlest spirit I know; Dmitro, one of my favorites; Zach, who will be relieved to know that he is also one of my favorites; and Brendan, who is a treasure. Thank you to Alex, Aubrey, Ashley, and Chad—Candace’s amazing friends who not only gave me their stamp of approval but became my friends, too. I am thankful to Erin for their care and wisdom. I also want to thank my comrades from Boston Feminists for Liberation, who have taught me so much.
Load more

Recommended publications
  • 6-[18 F] Fluoro-L-DOPA: a Well-Established Neurotracer with Expanding Application Spectrum and Strongly Improved Radiosyntheses
    Hindawi Publishing Corporation BioMed Research International Volume 2014, Article ID 674063, 12 pages http://dx.doi.org/10.1155/2014/674063 Review Article 6-[18F]Fluoro-L-DOPA: A Well-Established Neurotracer with Expanding Application Spectrum and Strongly Improved Radiosyntheses M. Pretze,1 C. Wängler,2 and B. Wängler1 1 Molecular Imaging and Radiochemistry, Department of Clinical Radiology and Nuclear Medicine, Medical Faculty Mannheim of Heidelberg University, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany 2 Biomedical Chemistry, Department of Clinical Radiology and Nuclear Medicine, Medical Faculty Mannheim of Heidelberg University, 68167 Mannheim, Germany Correspondence should be addressed to B. Wangler;¨ [email protected] Received 26 February 2014; Revised 17 April 2014; Accepted 18 April 2014; Published 28 May 2014 Academic Editor: Olaf Prante Copyright © 2014 M. Pretze et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 18 For many years, the main application of [ F]F-DOPA has been the PET imaging of neuropsychiatric diseases, movement disorders, and brain malignancies. Recent findings however point to very favorable results of this tracer for the imaging of other malignant diseases such as neuroendocrine tumors, pheochromocytoma, and pancreatic adenocarcinoma expanding its application spectrum. With the application of this tracer in neuroendocrine tumor imaging, improved radiosyntheses have been developed. Among these, 18 the no-carrier-added nucleophilic introduction of fluorine-18, especially, has gained increasing attention as it gives [ F]F-DOPA in higher specific activities and shorter reaction times by less intricate synthesis protocols.
    [Show full text]
  • Mrna Vaccine: a Potential Therapeutic Strategy Yang Wang† , Ziqi Zhang† , Jingwen Luo† , Xuejiao Han† , Yuquan Wei and Xiawei Wei*
    Wang et al. Molecular Cancer (2021) 20:33 https://doi.org/10.1186/s12943-021-01311-z REVIEW Open Access mRNA vaccine: a potential therapeutic strategy Yang Wang† , Ziqi Zhang† , Jingwen Luo† , Xuejiao Han† , Yuquan Wei and Xiawei Wei* Abstract mRNA vaccines have tremendous potential to fight against cancer and viral diseases due to superiorities in safety, efficacy and industrial production. In recent decades, we have witnessed the development of different kinds of mRNAs by sequence optimization to overcome the disadvantage of excessive mRNA immunogenicity, instability and inefficiency. Based on the immunological study, mRNA vaccines are coupled with immunologic adjuvant and various delivery strategies. Except for sequence optimization, the assistance of mRNA-delivering strategies is another method to stabilize mRNAs and improve their efficacy. The understanding of increasing the antigen reactiveness gains insight into mRNA-induced innate immunity and adaptive immunity without antibody-dependent enhancement activity. Therefore, to address the problem, scientists further exploited carrier-based mRNA vaccines (lipid-based delivery, polymer-based delivery, peptide-based delivery, virus-like replicon particle and cationic nanoemulsion), naked mRNA vaccines and dendritic cells-based mRNA vaccines. The article will discuss the molecular biology of mRNA vaccines and underlying anti-virus and anti-tumor mechanisms, with an introduction of their immunological phenomena, delivery strategies, their importance on Corona Virus Disease 2019 (COVID-19) and related clinical trials against cancer and viral diseases. Finally, we will discuss the challenge of mRNA vaccines against bacterial and parasitic diseases. Keywords: mRNA vaccine, Self-amplifying RNA, Non-replicating mRNA, Modification, Immunogenicity, Delivery strategy, COVID-19 mRNA vaccine, Clinical trials, Antibody-dependent enhancement, Dendritic cell targeting Introduction scientists are seeking to develop effective cancer vac- A vaccine stimulates the immune response of the body’s cines.
    [Show full text]
  • A Review of COVID-19 Vaccines in Development: 6 Months Into the Pandemic
    Article Review A review of COVID-19 vaccines in development: 6 months into the pandemic Merlin Sanicas, Melvin Sanicas, Doudou Diop, Emanuele Montomoli Corresponding author: Doudou Diop, PATH, Dakar, Sénégal. [email protected] Received: 13 Jul 2020 - Accepted: 29 Jul 2020 - Published: 05 Oct 2020 Keywords: Coronavirus, COVID-19, pandemic, vaccine development Copyright: Merlin Sanicas et al. Pan African Medical Journal (ISSN: 1937-8688). This is an Open Access article distributed under the terms of the Creative Commons Attribution International 4.0 License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Cite this article: Merlin Sanicas et al. A review of COVID-19 vaccines in development: 6 months into the pandemic. Pan African Medical Journal. 2020;37(124). 10.11604/pamj.2020.37.124.24973 Available online at: https://www.panafrican-med-journal.com/content/article/37/124/full A review of COVID-19 vaccines in development: 6 Abstract months into the pandemic 1 2 3,& The advent of the COVID-19 pandemic and the Merlin Sanicas , Melvin Sanicas , Doudou Diop , dynamics of its spread is unprecedented. 4,5 Emanuele Montomoli Therefore, the need for a vaccine against the virus is huge. Researchers worldwide are working 1Centre de Recherche en Cancérologie de around the clock to find a vaccine. Experts Marseille, Université Aix-Marseille, Marseille, 2 estimate that a fast-tracked vaccine development France, Clinical Development, Takeda process could speed a successful candidate to Pharmaceuticals International AG, Zurich, 3 4 market in approximately 12-18 months.
    [Show full text]
  • B-Cell Epitope Prediction for Peptide-Based Vaccine Design: Towards a Paradigm of Biological Outcomes for Global Health
    Caoili et al. Immunome Research 2011, 7:2:2 http://www.immunome-research.net/ RESEARCH Open Access B-cell epitope prediction for peptide-based vaccine design: towards a paradigm of biological outcomes for global health Salvador Eugenio C. Caoili Abstract Global health must address a rapidly evolving burden of disease, hence the urgent need for versatile generic technologies exemplified by peptide-based vaccines. B-cell epitope prediction is crucial for designing such vaccines; yet this approach has thus far been largely unsuccessful, prompting further inquiry into the underly- ing reasons for its apparent inadequacy. Two major obstacles to the development of B-cell epitope prediction for peptide-based vaccine design are (1) the prevailing binary classification paradigm, which mandates the problematic dichotomization of continuous outcome variables, and (2) failure to explicitly model biological consequences of immunization that are relevant to practical considerations of safety and efficacy. The first obstacle is eliminated by redefining the predictive task as quantitative estimation of empirically observable biological effects of antibody-antigen binding, such that prediction is benchmarked using measures of corre- lation between continuous rather than dichotomous variables; but this alternative approach by itself fails to address the second obstacle even if benchmark data are selected to exclusively reflect functionally relevant cross-reactivity of antipeptide antibodies with protein antigens (as evidenced by antibody-modulated protein biological activity), particularly where only antibody-antigen binding is actually predicted as a surrogate for its biological effects. To overcome the second obstacle, the prerequisite is deliberate effort to predict, a priori, biological outcomes that are of immediate practical significance from the perspective of vaccination.
    [Show full text]
  • Heterosubtypic Influenza Protection Elicited by Double-Layered
    Heterosubtypic influenza protection elicited by double- layered polypeptide nanoparticles in mice Lei Denga, Timothy Z. Changb, Ye Wanga, Song Lib, Shelly Wangc, Shingo Matsuyamaa, Guoying Yud, Richard W. Compansc, Jian-Dong Lia, Mark R. Prausnitzb, Julie A. Championb, and Bao-Zhong Wanga,1 aCenter for Inflammation, Immunity & Infection, Georgia State University Institute for Biomedical Sciences, Atlanta, GA 30303; bSchool of Chemical & Biomolecular Engineering, Georgia Institute of Technology, Atlanta, GA 30332; cEmory Vaccine Center, Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30307; and dState Key Laboratory of Fibrosis Biology, College of Life Science, Henan Normal University, Xinxiang, 453002 Henan, China Edited by Peter Palese, Icahn School of Medicine at Mount Sinai, New York, NY, and approved July 9, 2018 (received for review April 5, 2018) Influenza is a persistent threat to public health. Here we report required for complete protection against a lethal influenza A that double-layered peptide nanoparticles induced robust specific challenge (14). immunity and protected mice against heterosubtypic influenza A Nanotechnology provides a promising approach for the de- virus challenges. We fabricated the nanoparticles by desolvating a velopment of new generations of influenza vaccines. Physiolog- composite peptide of tandem copies of nucleoprotein epitopes into ically activated disassembling nanoparticles mimic the biophysical nanoparticles as cores and cross-linking another composite peptide of and biochemical cues of virions and initiate “danger” signals that four tandem copies of influenza matrix protein 2 ectodomain epitopes enhance the activation of innate immunity and elicit potent cellular to the core surfaces as a coating. Delivering the nanoparticles via dis- and humoral immune responses with minimal cytotoxicity (15).
    [Show full text]
  • Plant-Made HIV Vaccines and Potential Candidates
    Plant-made HIV vaccines and potential candidates Jocelyne Tremouillaux-Guiller1, Khaled Moustafa2, Kathleen Hefferon3, Goabaone Gaobotse4, and Abdullah Makhzoum4 1Faculty of Pharmaceutical Sciences, University François Rabelais, Tours, France. 2Arabic Science Archive – ArabiXiv (https://arabixiv.org). 3Department of Microbiology, Cornell University, USA. 4Department of Biological Sciences & Biotechnology, Botswana International University of Science & Technology, Botswana. Correspondence: [email protected]; [email protected] Highlights HIV/AIDS is a partially treatable but not completely curable pandemic disease. Major advances have been made to treat patients living with HIV/AIDS. Developing HIV vaccines is an ongoing endeavor and moves at an accelerated pace Plant molecular pharming is a valuable tool in HIV/AIDS vaccine research. Abstract Millions of people around the world suffer from heavy social and health burdens related to HIV/AIDS and its associated opportunistic infections. To reduce these burdens, preventive and therapeutic vaccines are required. Effective HIV vaccines have been under investigation for several decades using different animal models. Potential plant-made HIV vaccine candidates have also gained attention in the past few years. In addition to this, broadly neutralizing antibodies produced in plants which can target conserved viral epitopes and neutralize mutating HIV strains have been identified. Numerous epitopes of glycoproteins and capsid proteins of HIV-1 are a part of HIV therapy. Here, we discuss some recent findings aiming to produce anti-HIV-1 recombinant proteins in engineered plants for AIDS prophylactics and therapeutic treatments. Keywords: plant made pharmaceuticals; HIV vaccine; AIDS drug; plant molecular pharming/farming; multiepitopic HIV vaccine. 1 Introduction Acquired Immunodeficiency Syndrome (AIDS) is one of the greatest challenges to global public health today.
    [Show full text]
  • Vaccination in Developing Countries: Problems, Challenges and Opportunities - T
    GLOBAL PERSPECTIVES IN HEALTH - Vol. II - Vaccination in Developing Countries: Problems, Challenges and Opportunities - T. Pang VACCINATION IN DEVELOPING COUNTRIES: PROBLEMS, CHALLENGES, AND OPPORTUNITIES T. Pang Department of Research Policy and Cooperation, World Health Organization, Geneva, Switzerland Keywords: Developing countries, vaccination, immunization Contents 1. Introduction 2. Challenges to Improving Vaccination 3. Obstacles to Effective Vaccination 4. Solutions to Problems of Access and Coverage 5. Mechanisms: Cooperation Between Industrialized Nations and Developing Nations 6. Recent Initiatives—A Brighter Future? 6.1. The International Vaccine Institute 6.2. Global Alliance for Vaccines and Immunization 6.3. Millennium Vaccine Initiative 6.4. International AIDS Vaccine Initiative 6.5. Malaria Vaccine Initiative 7. Role of the World Health Organization 8. The Future Glossary Bibliography Biographical Sketch Summary Vaccines are the most inexpensive means of improving health and lowering morbidity and mortality caused by infectious diseases in the developing world. However, and in spite of significant advances in science and technology, the implementation of global vaccination coverage remains a pipe dream. Many obstacles and challenges remain, and imaginative and bold solutions are required. Recent initiatives based on international cooperation,UNESCO philanthropy, and goodwill – promise EOLSS a brighter future for those in need living in the developing world. 1. IntroductionSAMPLE CHAPTERS The eradication of smallpox and the imminent demise of polio are clear reminders of the power of vaccination in dealing with the scourge of communicable diseases in the developing world. The World Health Organization’s (WHO) Expanded Program for Immunization (EPI), which is focused on the six major diseases of childhood (diphtheria, pertussis, tetanus, polio, measles, and tuberculosis), succeeded in dramatically raising immunization coverage in developing countries from 5% in the 1970s to more than 80% of the birth cohort in the 1990s.
    [Show full text]
  • Peptide Handbook a Guide to Peptide Design and Applications in Biomedical Research
    Peptide Handbook A Guide to Peptide Design and Applications in Biomedical Research First Edition www.GenScript.com GenScript USA Inc. 860 Centennial Ave. Piscataway, NJ 08854 USA Phone: 1-732-885-9188 Toll-Free: 1-877-436-7274 Fax: 1-732-885-5878 Table of Contents The Universe of Peptides Reliable Synthesis of High-Quality Peptides Molecular structure 3 by GenScript Characteristics 5 Categories and biological functions 8 Analytical methods 10 Application of Peptides Research in structural biology 12 Research in disease pathogenesis 12 Generating antibodies 13 FlexPeptideTM Peptide Synthesis Platform which takes advantage of the latest Vaccine development 14 peptide synthesis technologies generates a large capacity for the quick Drug discovery and development 15 synthesis of high-quality peptides in a variety of lengths, quantities, purities Immunotherapy 17 and modifications. Cell penetration-based applications 18 Anti-microorganisms applications 19 Total Quality Management System based on multiple rounds of MS and HPLC Tissue engineering and regenerative medicine 20 analyses during and after peptide synthesis ensures the synthesis of Cosmetics 21 high-quality peptides free of contaminants, and provides reports on peptide Food industry 21 solubility, quality and content. Synthesis of Peptides Diverse Delivery Options help customers plan their peptide-based research Chemical synthesis 23 according to their time schedule and with peace of mind. Microwave-assisted technology 24 ArgonShield™ Packing eliminates the experimental variation caused by Ligation technology 26 oxidization and deliquescence of custom peptides through an innovative Recombinant technology 28 Modifications packing and delivery technology. 28 Purification 30 Expert Support offered by Ph.D.-level scientists guides customers from Product identity and quality control 31 peptide design and synthesis to reconstitution and application.
    [Show full text]
  • HIV Envelope Antigen Valency on Peptide Nanofibers
    www.nature.com/scientificreports OPEN HIV envelope antigen valency on peptide nanofbers modulates antibody magnitude and binding breadth Chelsea N. Fries1,9, Jui‑Lin Chen2,3,9, Maria L. Dennis3, Nicole L. Votaw1, Joshua Eudailey3, Brian E. Watts3, Kelly M. Hainline1, Derek W. Cain3, Richard Barfeld4, Cliburn Chan4, M. Anthony Moody3,5,6, Barton F. Haynes3,6, Kevin O. Saunders2,3,6,7, Sallie R. Permar2,3,5,6,8, Genevieve G. Fouda2,3,5* & Joel H. Collier1,6* A major challenge in developing an efective vaccine against HIV‑1 is the genetic diversity of its viral envelope. Because of the broad range of sequences exhibited by HIV‑1 strains, protective antibodies must be able to bind and neutralize a widely mutated viral envelope protein. No vaccine has yet been designed which induces broadly neutralizing or protective immune responses against HIV in humans. Nanomaterial‑based vaccines have shown the ability to generate antibody and cellular immune responses of increased breadth and neutralization potency. Thus, we have developed supramolecular nanofber‑based immunogens bearing the HIV gp120 envelope glycoprotein. These immunogens generated antibody responses that had increased magnitude and binding breadth compared to soluble gp120. By varying gp120 density on nanofbers, we determined that increased antigen valency was associated with increased antibody magnitude and germinal center responses. This study presents a proof‑of‑concept for a nanofber vaccine platform generating broad, high binding antibody responses against the HIV‑1 envelope glycoprotein. HIV-1/AIDS has been responsible for 30 million deaths since it became a global pandemic1. Despite decades of research, a vaccine against HIV-1 has remained elusive.
    [Show full text]
  • UK Automated Synthesis Forum 2017 Agenda
    “The primary showcase of chemical technologies since 1996” UK Automated Synthesis Forum 2017 Agenda Tuesday, 7th November 2017 10:00am Introductory Remarks Jason Tierney, Charles River, Chair UKASF 10:10am Welcome Remarks Paul Kendall, Festo 10:20am Plenary Lecture: Earth, Wind, Fire and Light - New Technologies Enabling Chemical Innovation Dr. Ian W Davies, Princeton 11:20am Coffee & Networking Metabolite Synthesis and purification Chair: Andrew Ledgard (Lilly) / Paul Blaney (Concept Life Sciences) 11:40am The Generation and Identification of Biosynthetic Metabolites Dr. Scott Martin and Dr. Eva Lenz, AstraZeneca 12:00pm Reaction Screening Tools for Medicinal Chemistry Marc Bazin, Hepatochem 12:20pm Challenges associated with small scale purification of metabolites and impurities Ronan Cleary, Waters Ltd 12.40pm Lunch, Exhibition & Networking Flow Chemistry I Chair: Paul Turner (AZ) / John Taylor (Beatson Institute) 2:30pm Using Open-Source Hardware and Software Technologies to Automate Chemical Synthesis Dr. Matthew O’Brien, University of Keele. 2:50pm Practical Organic Electrosynthesis in Laboratory Flow Electrolysis Cell with Extended Channels: Milligrammes to Multigrammes/Hour Prof. Richard Brown, University of Southampton 3:10pm Research towards Automated Continuous Flow Peptide Synthesis (Vapourtec) Dr. Nikzad Nikbin, New Path Molecular 3:30pm Photochemical reactors for both batch and flow Martyn Fordham, Asynt/Uniqsis 3:50-4:10pm Break New Technologies I Jason Tierney (Charles River) / Tobias Mochel (Sygnature Discovery) “The primary showcase of chemical technologies since 1996” 4:10pm What could be driving the lab of the future and is the ‘Smart Lab’ really a thing? Paul Kendall, Festo 4:30pm ElectraSyn 2.0: Facilitating the mass adoption of electrochemistry for preparative organic synthesis Kevin Mann, IKA 4:50pm Mya 4, the new Reaction Station from Radleys Dr.
    [Show full text]
  • Optimisation of Synthesis, Purification and Reformulation of (R)-[N-Methyl-11C]PK11195 for in Vivo PET Imaging Studies
    Optimisation of Synthesis, Purification and Reformulation of (R)-[N-methyl-11C]PK11195 for In Vivo PET Imaging Studies Vítor Hugo Pereira Alves Integrated Master in Biomedical Engineering Physics Department Faculty of Sciences and Technology of University of Coimbra 2012 To my Parents, Optimisation of Synthesis, Purification and Reformulation of (R)-[N-methyl-11C]PK11195 for In Vivo PET Imaging Studies Vítor Hugo Pereira Alves Supervisor: Miguel de Sá e Sousa Castelo Branco Co-supervisor: Antero José Pena Afonso de Abrunhosa Dissertation presented to the Faculty of Sciences and Technology of the University of Coimbra to obtain a Master’s degree in Biomedical Engineering Physics Department Faculty of Sciences and Technology of University of Coimbra 2012 This copy of the thesis has been supplied on condition that anyone who consults it is understood to recognize that its copyright rests with its author and that no quotation from the thesis and no information derived from it may be published without proper acknowledgement. i Acknowledgments First of all, I would like to express my gratitude to Professor Antero Abrunhosa, for the opportunity given to carry out this work, for all the knowledge and for the full confidence. More than a project supervisor, he was a friend and excellent professor for his support and encouragement to reach the defined goals. To Professor Miguel Castelo-Branco, director of the Institute for Nuclear Sciences Applied to Health and also supervisor of this work for all support and interest in this project. To Professor Francisco Alves, I am grateful for his full availability to help, and for all the times that I asked for carbon-11.
    [Show full text]
  • Combined Approaches to the Synthesis and Study of Glycoproteins
    REVIEW Combined Approaches to the Synthesis and Study of Glycoproteins Gonc¸alo J. L. Bernardes†, Bastien Castagner‡, and Peter H. Seeberger†,* †Department of Biomolecular Systems, Max-Planck Institute of Colloids and Interfaces, Research Campus Golm, 14424 Potsdam, Germany, and ‡Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology (ETH Zu¨rich), Wolfgang-Pauli-Str. 10, 8093 Zu¨rich, Switzerland arbohydrates constitute a large and diverse class of biopolymers. For a long time the pri- ABSTRACT Carbohydrates are the basis for many therapeutic and diagnostic C mary role of carbohydrates in biology was strategies, yet the full potential of glycans in medicine has not been realized. The viewed as a source of energy or as an integral part of cel- study of the precise role of different carbohydrates, bound to either proteins or lip- lular structure. However, over recent decades, it has be- ids, is hampered by difficulties in accessing pure, well-defined glycoconjugates. come clear that the expression of complex carbohy- This Review highlights recent advances in glycobiology with a particular empha- drates in human cells is critical in the development and sis on oligosaccharide synthesis and conjugation techniques for the construction physiology of living systems (1−4). The mammalian gly- of homogeneous glycoconjugates. New methods for the study of proteinϪglycan come is thought to be complex, due to the inherent interactions such as carbohydrate arrays and in vivo visualization of glycosylation structural diversity of carbohydrate molecules (5). Na- pattern changes will also be addressed. The development of glycotherapeutics is ture uses this abundant repertoire of structures as spe- just beginning, and much remains to be understood about the relationship be- cific codes in several biological processes such as cellu- tween glycoconjugate structure and function.
    [Show full text]