Navigation Links
Scripps Research team creates new synthetic compound with HIV-fighting promise

LA JOLLA, CA January 18, 2011 Using chemical compounds found in a Japanese plant as a lead and the clever application of ultraviolet light, a Scripps Research Institute team has created a unique library of dozens of synthetic compounds to test for biomedical potential. Already, one of the compounds has shown great promise in inhibiting replication of HIV particles and fighting inflammation.

With the report of their work scheduled to appear in the online Early Edition of Proceedings of the National Academy of Sciences this week, the researchers now plan to optimize the compound's pharmaceutical potential so that it can be pursued as a drug candidate.

The plant Hypericum chinense, known in Japan as biyouyanagi, produces beautiful yellow flowers and, as it happens, potent chemical compounds known as biyouyanagins that have already shown promising anti-HIV and anti-tumor activity. That got the attention of K.C. Nicolaou, who holds the titles chair of the Department of Chemistry, Aline W. and L.S. Skaggs Professor of Chemical Biology, and Darlene Shiley Chair in Chemistry at Scripps Research. Nicolaou's interest was also piqued because the plant is from the same family that produces St. John's wort, and the biyouyanagins possess an intriguing molecular architecture.

"It was the perfect recipe for convincing a synthetic chemist to get into the game," said Nicolaou, who spearheaded the project in collaboration with a number of Scripps Research colleagues. "It seemed like there was so much to be discovered."

Best of Both Worlds

Within the biomedical field there are some researchers that argue natural products are the best route to new drug discovery. Others laud the potential of designing completely synthetic drugs. "I belong to both camps," says Nicolaou, because he prefers to start with natural products and then modify them in a variety of ways to create new synthetic products with improved potential. "The power of this method is that it allows us to build on the natural structures to make a whole new and diverse family of compounds."

An unexpected side result of the group's initial work was the discovery that the structure previously reported for the biyouyanagins was slightly off. With the proper structures in hand, the Nicolaou team recognized it could induce formation of critical bonds that join the two domains of the molecules by bombarding the right chemical building blocks with ultraviolet light.

This technique, known as photocycloaddition, allowed the scientists to synthesize the two known biyouyanagins as well as a third type not yet discovered in nature. The scientists then began combining a variety of different building blockssome commercially available and others they produced in the labusing the photocycloaddition to build a library of about 50 analogs, compounds similar to the originals but with significant chemical variations.

The resulting compounds then went in groups to various collaborating Scripps Research laboratories. Professor Dennis Burton's lab analyzed the compounds' ability to inhibit replication of HIV. Chair of the Department of Chemical Physiology Ben Cravatt's team looked at anti-inflammatory potential. Professor Juan de la Torre's group examined effects against LCMV, the prototype member of the arenavirus family that includes several causative agents of deadly hemorrhagic fever disease in West Africa and South America.

All of the compounds in the team's new library are, like aspirin, considered small molecules. Nicolaou believes these offer the best biomedical potential. Larger molecules such as proteins are finding new medical applications, but have to be injected and are often short-lived and very expensive.

"If you can discover small molecules that work, they're affordable and they last long enough in the body to do their jobs," he said. "Those are the magic bullets."

A Promising Lead

One compound from the new library, number 53, stood out. One side of its structure is essentially the same as that of a natural biyouyanagin, while the other side is a departure comprising a structural motif like the bases found in DNA. In the HIV testing, it compared favorably with the well-known AIDS drug AZT, though it is not yet as potent. In the anti-inflammatory tests, it was as potent or more so than commercially available products. This particular compound hasn't been tested for its potential against arenaviruses, but Nicolaou is hopeful the team will eventually find interesting activity there as well.

"We were certainly excited to see those results," says Nicolaou. "It's quite a promising lead." Next, the team will tinker with 53's initial structure in search of modifications that will increase its potency. Once its biomedical activities are optimized, the group will consider pushing the compound toward the drug-testing process.


Contact: Mika Ono
Scripps Research Institute

Related biology news :

1. Scripps Research and Vanderbilt to launch joint institute
2. Scripps Research chemist devises new method to quantify protein changes
3. Scripps Research scientists identify key interaction in hepatitis C virus
4. Scripps Research scientist uncovers switch controlling protein production
5. Scripps Research scientists show prions mutate and adapt to host environment
6. Scripps scientists see the light in bizarre bioluminescent snail
7. Scripps Research scientists redefine the role of plasma cells in the immune system
8. Judy and J. John Goodman give $50,000 gift to Scripps Florida
9. New Scripps Florida scientist awarded pair of unconventional grants
10. Scripps Research scientists identify new mechanism regulating daily biological rhythms
11. Scripps Research team watches formation of cells protein factories for first time
Post Your Comments:
(Date:11/4/2015)... , November 4, 2015 ... market report published by Transparency Market Research "Home Security Solutions ... and Forecast 2015 - 2022", the global home security solutions ... bn by 2022. The market is estimated to expand ... from 2015 to 2022. Rising security needs among customers ...
(Date:10/29/2015)... Oct. 29, 2015  Rubicon Genomics, Inc., today ... distribution of its DNA library preparation products, including ... new ThruPLEX Plasma-seq kit. ThruPLEX Plasma-seq has been ... of NGS libraries for liquid biopsies--the analysis of ... prognostic applications in cancer and other conditions. Eurofins ...
(Date:10/27/2015)... -- Munich, Germany , October ... automatically maps data from mobile eye tracking videos created ... that they can be quantitatively analyzed with SMI,s analysis ... , October 28-29, 2015. SMI,s Automated Semantic Gaze ... tracking videos created with SMI,s Eye Tracking Glasses ...
Breaking Biology News(10 mins):
(Date:11/26/2015)... , November 26, 2015 /PRNewswire/ ... --> Accutest Research Laboratories, ... Contract Research Organization (CRO), has formed ... Cancer Center - Temple Health for ... ,     (Photo: ) , ...
(Date:11/25/2015)... , Nov. 25, 2015  PharmAthene, Inc. (NYSE MKT: ... adopted a stockholder rights plan (Rights Plan) in an ... loss carryforwards (NOLs) under Section 382 of the Internal ... --> PharmAthene,s use of its NOLs could be ... as defined in Section 382 of the Code. In ...
(Date:11/25/2015)... HOLLISTON, Mass. , Nov. 25, 2015 ... a biotechnology company developing bioengineered organ implants for life-threatening ... will present at the LD Micro "Main Event" investor ... PT. The presentation will be webcast live and posted ... also be available at the conference for one-on-one meetings ...
(Date:11/25/2015)... , ... November 25, 2015 , ... ... the Organization of Black Aerospace Professionals (OPBAP) has been formalized with the signing ... AMA team leaders met with OPBAP leaders Capt. Karl Minter and Capt. Albert ...
Breaking Biology Technology: