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PCI RECOGNIZES FACULTY TRAILBLAZERS
“Amos Smith, William Warren Rhodes-Robert J. Thompson Professor of Chemistry, was named Inventor of the Year. Smith is a world-renowned chemist who researches how to synthesize natural products, bioorganic chemistry, and materials science. More than 85 architecturally complex natural products have been prepared in his laboratory, and he has coauthored over 700 publications and 26 patents.
“Smith has been involved in the synthesis and development of numerous drug candidates and medicinal molecules, and is very well known in the field with an extensive IP portfolio,” says John Swartley, PCI’s Associate Vice Provost for Research and Managing Director.”
HIV-1 envelope glycoproteins protect themselves by adopting a sealed shape, similar to a “closed can.” By using a cocktail of small molecules (blue) and specific antibodies (green), researchers were able to visualize this “open can” for the first time. When the envelope of the virus adopts this shape, it becomes susceptible to antibody attack (Credit: Jonathan Richard, CRCHUM).
“If the human immunodeficiency virus (HIV) can be pictured as a sealed tin can, what would you see if you broke it open? An international team led by researchers at the University of Montreal Hospital Research Centre (CRCHUM), Tufts University, the University of Melbourne, and the University of Pennsylvania visualized for the first time how this “open can” adopts a shape that was unknown until now, providing a detailed image of the vulnerabilities of the virus.
Published in the journal Cell Host and Microbe, this major breakthrough was made possible through the use of a molecular “can opener” to expose parts of the virus envelope that can be targeted by antibodies.
“The characterization of the new shape of the envelope of the virus reveals unique details about the vulnerability of HIV that might be useful in strategies aimed at its eradication. It certainly opens new paths in the fight against this deadly virus,” says Andrés Finzi, one of the lead authors of the study, a researcher at the CRCHUM, and a professor at Université de Montréal.
When HIV infects cells of the human immune system, it attaches itself to specific receptors on these cells, CD4 and CCR5, using its envelope “spike.” Binding to the CD4 receptor triggers changes in the shape of the envelope that allow the virus to infect the host cell.
The new research describes the use of small-molecule CD4-mimetic compounds designed and synthesized at Penn’s Department of Chemistry to force the virus to open up and to expose vulnerable parts of its envelope, allowing the immune system cells to kill the infected cells. “This new research was made possible by compounds which were designed and synthesized here at Penn and is work that has been built upon by a number of collaborators from the above institutions,” says Amos B. Smith III.
In an earlier study published in PNAS in 2015, research led by Finzi showed that exposing the vulnerable parts of the envelope facilitates the elimination of infected cells by a mechanism known as antibody-dependent cellular cytotoxicity (ADCC).
Tufts University School of Medicine researchers were able to visualize the previously unknown shape of the virus envelope using a new technology: single-molecule Förster resonance energy transfer, or smFRET—that allows researchers to see how distinct elements of the envelope move with respect to one another. This provides a direct method for seeing that the HIV envelope is a dynamic machine with moving parts that allows it to adopt different shapes in response to different stimuli like antibodies or small molecules.
“We hope that visualizing the virus envelope’s shape will help in the development of vaccine candidates that specifically exploit ADCC. In the Thai vaccine trial (to date the only vaccine trial that showed a modest level of protection from HIV infection), generation of antibodies with ADCC activity was one factor correlated with protection from the virus,” says James Munro, a lead author of the study and assistant professor of molecular biology and microbiology at Tufts University School of Medicine. Munro was part of the team that pioneered the use of smFRET to better understand how the HIV-1 virus infects a human cell in real time.
The smFRET results were confirmed using cryo-electron microscopy (cryo-EM), a technique adopted by Isabelle Rouiller, a lead author of the study and a researcher at the University of Melbourne, that has recently gained recognition by the scientific community.
“It is fascinating how viruses protect themselves. Modern approaches such as single particle cryo-EM now allow us to look in detail at the molecular mechanisms developed through evolution. Directly visualizing the molecules at the surface of HIV will allow us to devise strategies to cure disease, a dream comes true!” says Rouiller.
In 2017, nearly 37 million people were infected with HIV worldwide. Every day, 5,000 new infections are reported to world health authorities.
Adapted from a news release provided by the Universite de Montreal, Tufts University School of Medicine, and the University of Melbourne.
This research was supported by the Canadian Institutes of Health Research, National Institute of Health Research, American Foundation for AIDS Research, National Institute of Allergy and Infectious Diseases of the National Institutes of Health (Grant 1K22AI116262), and the National Institutes of Health (Grant P01 GM056550).
Amos B. Smith III is the Rhodes-Thompson Professor of Chemistry in the Department of Chemistry in the School of Arts and Sciences at the University of Pennsylvania.”
Monday, June 18, 2018 – 17:00
Researchers at the Dana-Farber Cancer Institute, Beth Israel Deaconess Medical Center, Massachusetts General Hospital, Harvard Medical School, Duke University Medical Center, the University of Montreal and the University of Pennsylvania recently published two articles describing the use of small-molecule CD4-mimetic compounds to prevent infections by human immunodeficiency virus (HIV-1), the cause of acquired immunodeficiency syndrome (AIDS). The studies are published in the Journal of Infectious Diseases and Nature Communications.
The envelope (Env) spike on the surface of the HIV-1 membrane allows the virus to bind to receptors, CD4 and CCR5/CXCR4, on the target cell. Binding to the CD4 receptor triggers changes in the shape of Env that allow the virus to enter the host cell. This changing shape of Env, as well as variability among HIV-1 strains and a heavy carbohydrate coat, help HIV-1 to evade antibodies produced by the host immune system. These features of Env allow HIV-1 to establish persistent infections in humans and have made the development of protective vaccines extremely challenging. Antibodies that effectively block HIV-1 infection must recognize the pre-triggered form of Env, as it exists before binding the CD4 receptor. However, these antibodies cannot be elicited by current HIV-1 vaccine candidates. By contrast, antibodies against the triggered, CD4-bound form of Env are easily elicited by available vaccine candidates. However, these antibodies are ineffective at blocking HIV-1 infection. CD4-mimetic compounds are small molecules that bypass the defenses of HIV-1 and bind to Env in the same way as the CD4 receptor. The CD4-mimetic compounds prematurely trigger changes in the shape of Env that, at high doses, irreversibly inactivates the virus. The Journal of Infectious Diseases manuscript reports that this direct antiviral activity of a CD4-mimetic compound can protect BLT humanized mice from a vaginal exposure to HIV-1. At lower doses, the CD4-mimetic compounds make HIV-1 sensitive to inactivation by easily elicited antibodies. The Nature Communications manuscript shows that a CD4-mimetic compound allows an ineffectual vaccine to protect against a strong exposure to a distantly related immunodeficiency virus. The combination of a CD4-mimetic compound and a vaccine provides a high degree of protection from infection by viruses like HIV-1. Researchers are now exploring ways to deliver CD4-mimetic compounds in a sustained manner, for example through vaginal rings, to achieve potent protection against naturally acquired HIV-1 infection.
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1 A. M. Princiotto, V. D. Vrbanac, B. Melillo, J. Park, A. M. Tager, A. B. Smith, III, J. Sodroski and N. Madani. A Small-Molecule CD4 Mimetic Compound Protects BLT-mice From Human Immunodeficiency Virus Infection. J. Inf. Disease 2018. DOI/10.1093/intdis/jiyl74/4956145
N. Madani, A. M. Princiotto, L. Mach, S. Ding, J. Prevost, J. Richard, B. Hora, L. Sutherland, C.A. Zhao, B. P. Conn, T. Bradley, M. Anthony Moody, B. Melillo, A. Finzi, B. Haynes, A. B. Smith, III, S. Santra and J. Sodroski. A CD4-Mimetic Compound Enhances Vaccine Efficacy Against Stringent Immunodeficiency Virus Challenge. Nature Commun. 2018. (Published June 18, 2018).
Also see:
J. R. Courter, N. Madani, J. Sodroski, A. Schön, E. Freire, P. D. Kwong, W. A. Hendrickson, I. M. Chaiken, J. M. LaLonde and A. B. Smith, III. Structure-Based Design, Synthesis and Validation of CD4-Mimetic Small Molecule Inhibitors of HIV-1 Entry: Conversion of a Viral Entry Agonist to an Antagonist. Acc. Chem. Res. 2014, 47, 1228-1237.
Friday, December 29, 2017 – 09:27
Sunday, April 3, 2016 – 16:45
Thursday, July 23, 2015 – 12:37
The Philadelphia Organic Chemists’ Club and the Department of Chemistry at Penn invite you to attend a Symposium in honor of Professor Amos B. Smith, III, on Saturday, October 17th, 2015. Join us for a day of high caliber lectures on Recent Advances in Organic and Medicinal Chemistry. We will celebrate Professor Smith’s forty years of distinguished activity as a scholar at Penn and also his recent birthday! In recognition of the numerous milestone contributions he brought to our Science, Professor Smith will be presented with the 2015 Allan R. Day Award. To register, please send an email to pocclub.account@gmail.com. We hope to see you at the Symposium in October! On behalf of the organizers. Eugen Mesaros POCC Chair-Elect
Thursday, May 14, 2015 – 07:52
Dr. Amos B. Smith, III has been named the winner of the 2015 Perkin Prize for Organic Chemistry.
According to RSC’s website, he has been “Awarded for his continued outstanding contributions to new organic reaction development, complex natural product total synthesis, and new small molecules for medicinal chemistry.”
More information can be found on RSC’s website: http://www.rsc.org/ScienceAndTechnology/Awards/PerkinPrize/2015-Winner.asp
Tuesday, December 10, 2013 – 10:23
Dr. Carl Johnson (Introducer), and Symposium Presenters: Dr. Karl Hale, Dr. Amos Smith, Dr. John Wood and Dr. Yoshito Kishi.
Photo Credit: New York ACS http://www.newyorkacs.org/meetings/Nichols/NicholsEpilogue2014.php
September 15, 2013
In recognition of his outstanding achievement in chemical research, Amos B. Smith III of Penn Arts and Sciences has been named the recipient of the 2014 William H. Nichols Medal by the New York Section of the American Chemical Society (ACS). To date, 16 recipients of the Nichols Medal have also received the Nobel Prize.
Smith is the William Warren Rhodes–Robert J. Thompson Professor of Chemistry at Penn. His research focuses on three principal areas: development of innovative synthetic methods with wide application, demonstration of the utility of these synthetic tactics for the rapid construction of complex natural and unnatural products having significant bio-regulatory properties, and novel bio-organic/medicinal chemistry programs. In each area, Smith and his collaborators exploit the power of organic synthesis to improve human health. Completed and ongoing collaborations have contributed to the development of small-molecule probes for neurodegenerative diseases, bioavailable HIV-1 protease inhibitors, and small molecule inhibitors of the HIV cell entry process.
To date, more than 90 architecturally complex natural products have been prepared in the Smith laboratory. Smith was founding editor-in-chief of the ACS journal Organic Letters and has been on the editorial boards of many others. The recipient of dozens of awards, he has co-authored over 650 publications and 26 patents, and has delivered more than 600 invited lectures.
The world’s largest scientific society, ACS represents professionals at all degree levels and in all fields of chemistry and sciences that involve chemistry. The New York Section is one of the largest in the ACS.
The William H. Nichols Medal was created in 1902 by the New York Section to encourage original research by recognizing an outstanding contribution in the field of chemistry. Smith will receive his award at a research symposium next spring.
A list of previous winners can be found here.
Thursday, April 14, 2011 – 10:21
July 28, 2009 Professor Smith continues to be recognized for his lifetime of contributions to organic chemistry and chemical education.He was selected as member of the inaugural class of Fellows of the American Chemical Society. The ACS Fellows have demonstrated excellence in their contributions to the chemical sciences and in service to the ACS and the chemistry community. The 2009 Fellows were honored at a special ceremony during the ACS National Meeting in Washington, DC.
The ACS Fellows Program was created by the Board of Directors in December 2008 “to recognize members of the American Chemical Society for outstanding achievements in and contributions to Science, the Profession, and the Society.” Unlike ACS national awards, the distinguished honor of a Fellows designation will go to those who have distinguished themselves in multiple areas, including promoting the science, the profession, and service to the American Chemical Society. Ultimately, the body of Fellows is intended to reach approximately 1-2% of ACS membership.
For more information on the program, see: C&EN (Jan. 19, 2009, 87(3),70) or the ACS Program Page
Thursday, April 14, 2011 – 10:16
October 19, 2009 Amos B. Smith III, the William Warren Rhodes-Robert J. Thompson Professor of Chemistry, was recently awarded an honorary doctorate of science from Queen’s University Belfast in recognition of his distinguished contributions to the field of organic chemistry.
In delivering the citation at the ceremony in which Smith was honored, Professor Robbie Burch described Smith as an outstanding synthetic organic chemist. “He is distinguished for his exemplary research contributions to the field of organic synthesis and new reaction development, and to the application of new methodologies for the synthesis of natural products that have the potential to be the basis of new anticancer drugs,” said Burch. “This research has particular relevance to Northern Ireland and Queen’s University, where the internationally renowned Centre for Cancer Research and Cell Biology is based.”
Smith earned Bucknell University’s first combined four-year, bachelor’s-master’s degree in chemistry, receiving his doctorate in chemistry from Rockefeller University in 1972. He joined the Penn faculty the following year. Smith served as chemistry department chair from 1988 to 1996, and in 1998 he became the first editor-in-chief of the American Chemical Society journal Organic Letters. This year he was also selected as member of the inaugural class of Fellows of the American Chemical Society.
Thursday, April 14, 2011 – 10:12
November 2008 Amos B. Smith III MRSC, University of Pennsylvania, USA
Awarded for his many outstanding contributions to the total synthesis of complex natural products.
Amos Smith III undertook his two week lecture tour in November 2008, visiting a number of locations throughout the UK at which he delivered his Simonsen lecture.
Tuesday, October 24, 2006 – 12:41
April 24, 2006 Amos B. Smith, III, Rhodes-Thompson Professor of Chemistry and Member of the Monell Chemical Senses Center at the University of Pennsylvania, was elected to the American Academy of Sciences. (Click here for additional information.) Professor Smith obtained his early education at Bucknell University, receiving Bucknell’s first B.S.-M.S. combined degree in 1966-1967. After a year in Medical School at the University of Pennsylvania, he completed a Ph.D degree in Life Sciences at the Rockefeller University in 1972. In 1973, after a year as a Research Associate at Rockefeller, he joined the Department of Chemistry and the Monell Chemical Senses Center at the University of Pennsylvania. Currently he is the Rhodes-Thompson Professor of Chemistry and Member of the Monell Chemical Senses Center. From 1988 to 1996, he served as the Chairman of the Department of Chemistry. Professor Smith is also a Visiting Director and Honorary Member of the Kitasato Institute in Tokyo, Japan. In 1998 Professor Smith became the first Editor-in-Chief of a new American Chemical Society journal, Organic Letters, and in 2003 he was awarded the Yamada Prize from the Japan Research Foundation for Optically Active Compounds, Tokyo, Japan. Professor Smith’s research encompasses synthetic chemistry, bioorganic chemistry, and materials science. He is internationally known in particular for his outstanding achievements in the area of total synthesis of architecturally complex natural products having important bio-regulatory properties. To date, he and his coworker have published more than 515 publications in these areas. Over the course of 20 years, Professor Smith has accepted approximately 50 Japanese scientists into his laboratory at the University of Pennsylvania, where he has taught and fostered them in the broad area of chemistry. Professor Smith has also contributed significantly to academic exchanges between Japan and the U.S. by delivering lectures at Japanese universities and pharmaceutical companies. He visits Japan almost annually.
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Wednesday, November 3, 2004 – 16:20  November 3, 2004 Amos B. Smith, III, Rhodes-Thompson Professor of Chemistry and Member of the Monell Chemical Senses Center at the University of Pennsylvania, was honored with The Order of the Rising Sun, Gold Rays with Neck Ribbon for his outstanding contributions to the training and education of Japanese scientists and for the promotion of academic exchange between Japan and the United States. Professor Smith obtained his early education at Bucknell University, receiving Bucknell’s first B.S.-M.S. combined degree in 1966-1967. After a year in Medical School at the University of Pennsylvania, he completed a Ph.D degree in Life Sciences at the Rockefeller University in 1972. In 1973, after a year as a Research Associate at Rockefeller, he joined the Department of Chemistry and the Monell Chemical Senses Center at the University of Pennsylvania. Currently he is the Rhodes-Thompson Professor of Chemistry and Member of the Monell Chemical Senses Center. From 1988 to 1996, he served as the Chairman of the Department of Chemistry. Professor Smith is also a Visiting Director and Honorary Member of the Kitasato Institute in Tokyo, Japan. In 1998 Professor Smith became the first Editor-in-Chief of a new American Chemical Society journal, Organic Letters, and in 2003 he was awarded the Yamada Prize from the Japan Research Foundation for Optically Active Compounds, Tokyo, Japan. Professor Smith’s research encompasses synthetic chemistry, bioorganic chemistry, and materials science. He is internationally known in particular for his outstanding achievements in the area of total synthesis of architecturally complex natural products having important bio-regulatory properties. To date, he and his coworker have published more than 470 publications in these areas. Over the course of 20 years, Professor Smith has accepted approximately 50 Japanese scientists into his laboratory at the University of Pennsylvania, where he has taught and fostered them in the broad area of chemistry. Professor Smith has also contributed significantly to academic exchanges between Japan and the U.S. by delivering lectures at Japanese universities and pharmaceutical companies. He visits Japan almost annually. |