Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Computer Design Yields Better, More Efficient Therapeutic for Preventing Tissue Damage

26.08.2003


The tedious laboratory trial-and-error method for refining protein/peptide-based medicines could be accelerated and complemented by an innovative in silico (on computer) protein design method, according to researchers at Princeton University, the University of Pennsylvania School of Medicine, and the University of California at Riverside.



Their findings, appearing in a recent issue of the Journal of the American Chemical Society, could drastically decrease the time it takes to move potential biopharmaceuticals from the drawing board to the drug store. In this study, the researchers modeled a peptide (a chain of amino acids, such as a protein or protein fragment) called Compstatin, which prevents the autoimmune-mediated damage of organs during transplantation, and various inflammatory diseases. The computer modeling and optimization process cut down on trial and error and created a version of Compstatin seven times more efficient and stable than the original.

Since the function of a peptide depends on its form, the researchers modeled the effects of substituting each of Compstatin’s 13 amino acid subunits with a different amino acid. The novel in silico sequence design method could then model how the altered amino acid sequence folds together in comparison to the original peptide.


"It is a major challenge to design new peptides and proteins that exhibit the desired function such as improved inhibition for the complement system. The challenge centers around the problem of selecting promising sequences from the huge number of possible combinations and making sure those sequences will have the desired three-dimensional structure," said Christodoulos A. Floudas, PhD, a Professor of Chemical Engineering at Princeton University, whose laboratory developed the in silico de novo protein design approach. "At the heart of this innovative technology is a unique two-stage computer protein design method that not only selects and ranks sequences for a particular fold, but also validates the stability and specificity of the fold for these selected sequences."

"It would have taken us months - or even years - to synthesize and screen the 80 quadrillion possible peptide sequences that the protein design program considered," John D. Lambris, PhD, a professor in Penn’s Department of Pathology & Laboratory Medicine and a co-author on the study whose laboratory had discovered Compstatin in 1996. "In the end, we came up with two analogues to Compstatin - each created by altering one amino acid - that performed its job even better than the original protein."

Compstatin works by blocking human complement, the immune system’s passive alarm network that detects pathogens in the blood. Unfortunately, complement can also attack healthy tissue, and a variety of diseases are associated with complement gone awry, such as multiple sclerosis and hemolytic anemia. In addition, complement is thought to play a role in the destruction of cells during strokes, heart attacks, and burn injuries. The complement reaction is actually a series of interlocking cascades, or chain reactions, of biochemical events involving at least 30 proteins. Compstatin works by preventing the activation of C3, a protein that functions at the point where all the complement protein cascades intersect.

The two Compstatin analogues derived from the experiment are superior in their ability to cling to and, hence, prevent the activation of the C3 complement protein. Based on these two analogs, more Compstatin analogs have since been designed, some of which are 200 fold more active that the original Compstatin, according to Lambris. These new Compstatin analogs will be further refined and tested until ready for clinical trials.

To create templates of the desired shape for Compstatin, Dimitrios Morikis, PhD, a researcher at the Department of Chemical and Environmental Engineering of University of California, Riverside, identified the three-dimensional structure of Compstatin in solution via nuclear magnetic resonance (NMR) experiments, which he then computationally refined.

The computational de novo protein design system, developed at Princeton University by Floudas and postdoctoral associate John Klepeis, is a technological advance made possible by (i) a novel mixed-integer optimization model that narrows 200 trillion amino acid sequences into a short list of candidates that are likely to produce a peptide of the desired shape, and (ii) a system called ASTRO-FOLD that, using first-principles, predicts the structures that would be formed by the candidate sequences. The second step confirms and refines the first.

A distributed computing environment consisting of eighty Linux-based computers was used for all the computational predictions, and the predicted new peptides were subsequently synthesized and experimentally validated in the Lambris laboratory at Penn.

Greg Lester | University of Pennsylvania
Further information:
http://www.uphs.upenn.edu/news/News_Releases/august03/computer.htm

More articles from Life Sciences:

nachricht Molecular Force Sensors
20.09.2017 | Max-Planck-Institut für Biochemie

nachricht Foster tadpoles trigger parental instinct in poison frogs
20.09.2017 | Veterinärmedizinische Universität Wien

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Tiny lasers from a gallery of whispers

New technique promises tunable laser devices

Whispering gallery mode (WGM) resonators are used to make tiny micro-lasers, sensors, switches, routers and other devices. These tiny structures rely on a...

Im Focus: Ultrafast snapshots of relaxing electrons in solids

Using ultrafast flashes of laser and x-ray radiation, scientists at the Max Planck Institute of Quantum Optics (Garching, Germany) took snapshots of the briefest electron motion inside a solid material to date. The electron motion lasted only 750 billionths of the billionth of a second before it fainted, setting a new record of human capability to capture ultrafast processes inside solids!

When x-rays shine onto solid materials or large molecules, an electron is pushed away from its original place near the nucleus of the atom, leaving a hole...

Im Focus: Quantum Sensors Decipher Magnetic Ordering in a New Semiconducting Material

For the first time, physicists have successfully imaged spiral magnetic ordering in a multiferroic material. These materials are considered highly promising candidates for future data storage media. The researchers were able to prove their findings using unique quantum sensors that were developed at Basel University and that can analyze electromagnetic fields on the nanometer scale. The results – obtained by scientists from the University of Basel’s Department of Physics, the Swiss Nanoscience Institute, the University of Montpellier and several laboratories from University Paris-Saclay – were recently published in the journal Nature.

Multiferroics are materials that simultaneously react to electric and magnetic fields. These two properties are rarely found together, and their combined...

Im Focus: Fast, convenient & standardized: New lab innovation for automated tissue engineering & drug

MBM ScienceBridge GmbH successfully negotiated a license agreement between University Medical Center Göttingen (UMG) and the biotech company Tissue Systems Holding GmbH about commercial use of a multi-well tissue plate for automated and reliable tissue engineering & drug testing.

MBM ScienceBridge GmbH successfully negotiated a license agreement between University Medical Center Göttingen (UMG) and the biotech company Tissue Systems...

Im Focus: Silencing bacteria

HZI researchers pave the way for new agents that render hospital pathogens mute

Pathogenic bacteria are becoming resistant to common antibiotics to an ever increasing degree. One of the most difficult germs is Pseudomonas aeruginosa, a...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

“Lasers in Composites Symposium” in Aachen – from Science to Application

19.09.2017 | Event News

I-ESA 2018 – Call for Papers

12.09.2017 | Event News

EMBO at Basel Life, a new conference on current and emerging life science research

06.09.2017 | Event News

 
Latest News

Molecular Force Sensors

20.09.2017 | Life Sciences

Producing electricity during flight

20.09.2017 | Power and Electrical Engineering

Tiny lasers from a gallery of whispers

20.09.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>