Scripps Research Research Articles

Simplification of hallucinogen pays off

Salvinorin A, a hallucinogen produced by the Mexican plant Salvia divinorum, holds promise for treating itch and pain because it activates the kappa opioid receptor while avoiding the mu opioid receptor, a sister receptor that’s been associated with opioid abuse. Chemists have tried to synthesize salvinorin A so that they could alter the structure to sidestep the compound’s psychoactive effects while preserving its analgesic properties. But salvinorin A’s scaffold has been challenging to recreate. Now, a team of scientists at the California and Florida branches of Scripps Research Institute, as well as at the University of Southern California, report a 10-step total synthesis of 20-norsalvinorin A (ChemRxiv 2017, DOI: 10.26434/chemrxiv.5318188). The compound differs from salvinorin A by a single methyl group and binds to the kappa opioid receptor with an affinity similar to that of the natural product. When given to mice, it also relieves itch. The report is one

Cluster Preface: Recent Advances in Protein and Peptide Synthesis

Lei Liu received undergraduate training at the University of Science and Technology of China. He obtained his PhD degree at Columbia University in 2004 under the supervision of Prof. Ronald Breslow. He carried out post-doctoral studies at Scripps Research Institute from 2004 to 2007 in the laboratory of Prof. Chi-Huey Wong. He has been working at Tsinghua University since 2007. His research group studies chemical protein synthesis.

Secrets of abused stimulant revealed

In the Middle East, the stimulant fenethylline is widely abused by young people. Terrorist organizations such as the Islamic State give it to devotees to enhance their aggression, alertness, fearlessness, motivation, and physical performance. And terrorists involved in the 2015 Paris attacks are suspected to have taken the drug. When Kim D. Janda of Scripps Research Institute California learned about the fenethylline abuse issue, he wondered why addicts and terrorists latched onto the drug instead of its key metabolite, amphetamine, which acts similarly, is easier to synthesize, and is more readily available than fenethylline. Janda and his colleagues developed a new vaccine-based strategy to find out why. The method could also determine how other complex drugs and their metabolites work in the body. Fenethylline was first produced by a Degussa subsidiary in 1961 and went by several trade names, the best known of which is Captagon. Doctors in Europe prescribed

Supporting mental health

In the spring of 2016, Scripps Research Institute California graduate student Anna Owensby texted a friend: “I have this feeling right now that there isn’t really a place for me ... People like me aren’t supposed to get a Ph.D., we are addicts or homeless or in jail.” Owensby, 26, was a fourth-year graduate student. In her first years at Scripps, she was briefly hospitalized to evaluate her mental health, and she changed lab groups. Her new adviser, Scripps molecular medicine professor Dennis W. Wolan, had assisted in finding her a therapy group that seemed to be helping her. The group was not in Owensby’s insurance network, but Scripps was paying for the sessions. She passed her Ph.D. candidacy exam at the end of 2015, at which time her committee members indicated that she was progressing appropriately and that they had no nonacademic concerns about her. Then, in the space

A significant mechanism of molecular recognition between bioflavonoids and P-glycoprotein leading to herb-drug interactions

Inhibition of P-glycoprotein (P-gp)’s function may conduct significant changes in the prescription drugs’ pharmacokinetic profiles and escalate potential risks in taking place of drug/herb-drug interactions. Computational modeling was advanced to scrutinize some bioflavonoids which play roles in herb-drug interactions as P-gp inhibitors utilizing molecular docking and pharmacophore analyses. Twenty-five flavonoids were utilized as ligands for the modeling. The mouse P-gp (code: 4Q9H) was acquired from the PDB. The docking was operated utilizing AutoDock version 4.2.6 (Scripps Research Institute, La Jolla, CA) against the NBD2 of 4Q9H. The result illustrated the high correlation between the docking scores and observed activities of the flavonoids and the putative binding site of these flavonoids was proposed and compared with the site for ATP. To evaluate hotspot amino acid residues within the NBD2, Binding modes for the ligands were achieved using LigandScout to originate the NBD2-flavonoid pharmacophore models. The results asserted that these inhibitors competed with ATP for binding site in the NBD2 (as competitive inhibitors) including the hotspot residues which associated with electrostatic and van der Waals interactions with the flavonoids. In MD simulation of eight delegated complexes selected from the analyzed flavonoid subclasses, RMSD analysis of the trajectories indicated the residues were stable throughout the duration of simulations.

Design, Synthesis, and Biological Activity of New Triazole and Nitro-Triazole Derivatives as Antifungal Agents.

In this study two series of fluconazole derivatives bearing nitrotriazole (series A) or piperazine ethanol (series B) side chain were designed and synthesized and then docked in the active site of lanosterol 14α-demethylase enzyme (1EA1) using the Autodock 4.2 program (The scripps research institute, La Jolla, CA, USA). The structures of synthesized compound were confirmed by various methods including elemental and spectral (NMR, CHN, and Mass) analyses. Then antifungal activities of the synthesized compound were tested against several natural and clinical strains of fungi using a broth microdilution assay against several standard and clinical fungi. Nitrotriazole derivatives showed excellent and desirable antifungal activity against most of the tested fungi. Among the synthesized compounds, 5a–d and 5g, possessing nitrotriazole moiety, showed maximum antifungal activity, in particular against several fluconazole-resistant fungi.

Marijuana receptor caught in the act

Marijuana has been used both recreationally and as a drug for centuries, has been banned in many countries for decades, and has recently been legalized in some U.S. states. But researchers haven’t been able to get a high-resolution look at the way its active component, Δ9-tetrahydrocannabinol (Δ9-THC), interacts with its principal protein receptor in the body, cannabinoid receptor 1 (CB1). CB1 is a G protein-coupled receptor found mostly in central nervous system cell membranes. Last year, two groups managed to capture structures of CB1 bound to inhibitors and in a “switched off” state. Activated receptors break down more easily when manipulated, so they are harder to crystallize and analyze structurally. Now, one of the same groups—including Zhi-Jie Liu and Suwen Zhao of ShanghaiTech University, Laura M. Bohn of Scripps Research Institute Florida, and Alexandros Makriyannis of Northeastern University—has obtained high-resolution X-ray crystal structures of the receptor bound to two hydrocannabinol

ATVB Named Lecture Review-Insight Into Author: John H. Griffin.

ATVB Named Lecture Reviews—Sol Sherry Distinguished Lecture on Thrombosis Insight Into the Author: John H. Griffin, PhD, Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA During high school at Seattle Prep, my favorite subjects were physics, chemistry, and math; there it was emphasized that scholarship required a deep and fundamental knowledge of subjects. In the Jesuit tradition, academic excellence, curiosity, and service are inextricably entwined. During those years, I decided that my mission in life should be to discover new knowledge that would be intrinsically satisfying and that could also contribute to improving society. It seemed likely that being an eternal student in the academic life with the goal of making truly pioneering discoveries of potential utility could be fulfilling. My very supportive family, including my inspiring sisters, plus my mentors, close professional friends, and trainees have been critically important influences on my career development, and to all of them I am very grateful. For decades, my wife has provided limitless support to enable my own intense work efforts even while also providing her own model of …

New route to polysulfates, polysulfonates

Polysulfates and polysulfonates are exceptionally tough and impact resistant, making them useful engineering polymers. But they’ve rarely been used industrially because the chloride substitution chemistry often used to make carbon sulfate and carbon sulfonate links suffers from side reactions and is commercially impractical. Researchers now report that bifluoride salts are efficient and cost-effective catalysts for the synthesis of these tough materials (Nat. Chem. 2017, DOI: 10.1038/nchem.2796). The new chemistry, developed by K. Barry Sharpless and Peng Wu of Scripps Research Institute California, Jiajia Dong of the Shanghai Institute of Organic Chemistry, and coworkers, could potentially be scaled up to industrial levels. The new reaction is an extension of sulfur(VI) fluoride exchange (SuFEx), a click chemistry technique Sharpless and coworkers developed previously (Angew. Chem. Int. Ed. 2014, DOI: 10.1002/anie.201309399). The group initially used SuFEx, catalyzed by strongly basic “organosuperbases,”...

Cluster Preface: Asymmetric Brønsted Base Catalysis

Choon-Hong Tan is a professor at the Division of Chemistry and Biological Chemistry, Nanyang Technological University, Singapore. He received his BSc (Hons) First Class from the National University of Singapore (NUS) and his Phd from the University of Cambridge. He underwent postdoctoral training at the Department of Chemistry and Chemical Biology, Harvard University and the Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School. He began his independent career at the Department of Chemistry, National University of Singapore in 2003. Choon Hong has focused on the development of organocatalytic Brønsted base reactions that can be catalyzed with chiral guanidines. He has also demonstrated that pentanidiums (conjugated guanidiniums) are efficient phase-transfer catalysts. Recently, he described the use of chiral organic cations such as bisguanidiniums to modulate and activate anionic metallic salts. Benjamin List has been a director at the Max-Planck-Institut für Kohlenforschung since 2005. He obtained his Ph.D. in 1997 (Frankfurt). From 1997 until 1998 he conducted postdoctoral research at The Scripps Research Institute in La Jolla (USA) and became an assistant professor there in January 1999. In 2003 he joined the Max-Planck-Institut für Kohlenforschung. He has been an honorary professor at the University of Cologne since 2004. Ben List’s research focuses on organic synthesis and catalysis. He has contributed fundamental concepts to chemical synthesis including aminocatalysis, enamine catalysis, and asymmetric-counteranion-directed catalysis (ACDC). His latest work deals with chiral counteranions in asymmetric catalysis. This remarkably general strategy for asymmetric synthesis has recently found widespread use in organocatalysis, transition-metal catalysis, and Lewis acid catalysis.

Advances in Therapeutic Approaches to Extend Healthspan: a perspective from the 2nd Scripps Symposium on the Biology of Aging.

SummaryThe 2nd Scripps Florida Symposium on The Biology of Aging entitled ‘Advances in Therapeutic Approaches to Extend Healthspan’ was held on January 22nd–25th, 2017 at The Scripps Research Institute in Jupiter, Florida. The meeting highlighted a variety of therapeutic approaches in animal models of aging that either are or soon will be in clinic trials. For example, drugs targeting senescent cells, metformin, rapalogs, NAD precursors, young plasma, mitochondrial‐targeted free radical scavengers, stem cells, and stem cell factors all have shown significant preclinical efficacy. This perspective, based on presentations and discussions at the symposium, outlines the current and future state of development of therapeutic approaches to extend human healthspan.

Vancomycin triple threat antibiotic

Researchers have created a modified form of the approved antibacterial drug vancomycin (Vancocin) that has three independent mechanisms of action, boosting its potency and minimizing the potential for bacteria to develop resistance to it. Vancomycin, a bacterial natural product, had long been an antibiotic of last resort because it remained effective against drug-resistant bacteria after other medications stopped working. But bacteria have now evolved defenses against vancomycin, which works by inhibiting transpeptidase, an enzyme that catalyzes a cross-linking reaction bacteria use to build cell walls. Scientists have recently modified vancomycin in various ways to boost its potency and discourage resistance. In fact, the U.S. Food & Drug Administration recently approved three modified vancomycins: oritavancin, dalbavancin, and telavancin. They are each made by semisynthesis from vancomycin by chemical addition or modification of one or two chemical groups. Dale L. Boger of Scripps Research Institute and coworkers have now created what could

Scientific challenge and advances of the HIV vaccine research

After experiencing the failures of first and second generations of HIV vaccines, the RV144 trial in Thailand, combining pox virus and gp120 vaccines, shows a 31% protection for the first time in human study. The main scientific challenge to the vaccine of a Lentivirus where HIV belongs, is the lack of protective immunity in natural infection. Therefore, novel approaches have to be developed to overcome this bottleneck in evolution. Research progresses are made in the following areas: Finding the extremely broad neutralizing antibody (bNAb) and studying their maturation mechanism from the elite controller in HIV infected people; rational design of novel HIV immunogen to trigger germline B cells activation of the bNAb; stabilizing the HIV envelope trimers and enhancing their ability to induce bNAb; using replication competent vector to strengthen the immunogenicity and durability. Only four phase IIb/III clinical trials have been conducted in the first 30 years of HIV vaccine research. More than five phase IIb/III HIV vaccine clinical trials have been planned for the next 5 years. To repeat the RV144 trial in African, NIH started the P5 project of ALVAC/gp120 vaccine started in late 2016. The Harvard and Johnson’s collaborative Ad 26/GP140 vaccine trial will be initiated in 2017/2018. To compare the replicating (rTV) and non-replication (ALVAC) pox virus vector, China CDC and NIH will conduct a joint trial of combining their DNA/rTV with gP145 vaccines in China. The two funded CHAVI-ID groups led by Duke University and the Scripps Research Institute as well as the Vaccine Research Center of NIH will push their HIV env trimer vaccine to Phase IIb trials. With the past successes in the first two lentivirus (EIAV and FIV) vaccines and the 31% human protection of RV144, HIV vaccine research will definitely contribute to the course of Ending AIDS Epidemic by 2030.

Chemists among new NAS members for 2017

The National Academy of Sciences (NAS) elected 84 new members and 21 foreign associates in May. This brings the total active membership to 2,290 and the number of foreign associates—nonvoting members with citizenship outside the U.S.—to 475. Election to NAS, which is more than 150 years old, recognizes scientists and engineers for their distinguished and continuing achievements in original research and is considered one of the highest scientific honors bestowed in the U.S. This year, 21 of the newly elected are members of the American Chemical Society or work in areas related to the chemical sciences. The new U.S. members are Phaedon Avouris, IBM Thomas J. Watson Research Center (retired); Phil S. Baran, Scripps Research Institute, La Jolla, Calif.; Frank S. Bates, University of Minnesota, Twin Cities; Stephen B. Baylin, Johns Hopkins University; Sangeeta N. Bhatia, Massachusetts Institute of Technology; Dana Carroll, University of Utah School of Medicine; Geoffrey

HitGen works with Scripps and Calibr

HitGen, a biotech company based in China and with labs in Houston, will work with Scripps Research Institute and its affiliate, the California Institute for Biomedical Research (Calibr). The partners will use HitGen’s DNA-encoded small-molecule libraries to discover and develop oncology, regenerative medicine, and virology drugs. Scripps and Calibr will provide target materials and expertise. The alliance comes just one week after HitGen entered a multiyear drug discovery deal with Pfizer.

Patent highlights December 2016-January 2017.

Patent highlights December 2016-January 2017.

Profile of Ian A. Wilson

Viewed up close, antibodies, cellular receptors, and viral proteins may look like sloppy piles of spaghetti, fettucine, and fusilli to the untrained eye, but that’s not what Ian Wilson sees. “Protein structures are things of beauty, with their complex web of intricately positioned and interlocking elements that fold up precisely to generate a particular biological function,” says Ian Wilson, a professor of structural biology at The Scripps Research Institute in La Jolla, California. Ian Wilson. Image courtesy of BioMedical Graphics, The Scripps Research Institute. Broadly neutralizing antibody CR6261 bound to a hemagglutinin stem. Image courtesy of Marc-Andre Elsliger (The Scripps Research Institute, La Jolla, CA). Soluble HIV-1 envelope in complex with broadly neutralizing antibody PGT122. Image courtesy of Marc-Andre Elsliger (The Scripps Research Institute, La Jolla, CA). Wilson, who was elected a member of the National Academy of Sciences in 2016, has dedicated his career to solving the structures of immune system proteins. He hopes that these structures will provide insights into how the immune system interacts with and neutralizes human pathogens and, thus, how improved vaccines and therapies can be designed. Wilson grew up in Perth, Scotland, with his parents and sister. His father, who was a journalist, enlisted Wilson to help cover the major soccer matches in his home town. During live matches, Wilson would take his father’s copy covering the game and, every few minutes, dictate it by telephone to the local newspaper for evening publication. “He would also send me to local soccer matches, and I would have to write up 50 words and send it in within 10 minutes of the match finishing,” says Wilson. He adds that this practice was excellent training for his career, which can include impromptu speaking events and writing abstracts, grants, and papers. After earning a degree in biochemistry from …

Extending the reach of covalent drugs

The ability of covalent drugs to form strong bonds to protein targets tends to give them the advantage of long-lasting action. So far, covalent drug discovery has almost exclusively involved electrophilic small molecules that react with cysteine thiol groups (–SH) on proteins. The approved anticancer drug afatinib, for instance, is an electrophile that bonds covalently to a cysteine in epidermal growth factor receptor. A new study could help expand the reach of covalent drugs to nucleophiles. Cells often regulate proteins by using reactive oxygen species to oxidize cysteine thiols to cysteine sulfenic acids (–SOH). Cysteine oxidation makes thiol’s sulfur less reactive with electrophiles. About 15% of cellular cysteines are oxidized. To extend covalent drug discovery to cysteine-oxidized proteins, Kate Carroll of Scripps Research Institute Florida and coworkers recently developed a library of nucleophilic drug candidates. Compared with electrophiles, which react readily with nontarget biomolecules, nucleop...

Forging olefins via decarboxylation

Olefins are important components in many organic compounds, such as fragrances, natural products, and drugs. And while chemists have many ways of introducing double bonds into molecules, most rely on chemistry developed more than 30 years ago. Researchers led by Phil S. Baran of Scripps Research Institute California have now come up with a new way to introduce olefins into organic compounds (Nature 2017, DOI: 10.1038/nature22307). The reaction—known as decarboxylative alkenylation—starts with ubiquitous alkyl carboxylic acids. The chemists first transform the carboxylic acid into a redox-active ester, which then undergoes nucleophilic attack from an alkenyl zinc reagent in the presence of a nickel or iron catalyst. The whole process takes place in a single pot and can be used to make mono-, di-, tri-, and tetrasubstituted olefins. The reaction also allows exquisite control of olefin geometry because it is established by the geometry of the alkenyl zinc reagent rather than

Bring on the boron

Boron—the beloved oddball of the periodic table—can do some unique chemistry, thanks to its empty p orbital. This has made boronic acids and boronate esters indispensable components in many compounds, such as in partners for Suzuki cross-coupling reactions, in polymers, and even in a few drugs, such as the cancer therapies bortezomib (Velcade) and ixazomib (Ninlaro). But, while there are a few ways to make boronic acids and boronate esters, none is trivial. Phil S. Baran’s group at Scripps Research Institute California, has now come up with a simple and practical method for converting carboxylic acids into boronate esters and boronic acids (Science 2017, DOI: 10.1126/science.aam7355). The method works on primary, secondary, and tertiary carboxylic acids, as well as with peptidic and even natural product-derived substrates. It also tolerates a broad range of functional groups, so it can be used in the final steps of the synthesis of a densely