Synthetic peptoids instead of antibodies
Scientists at the University of Texas Southwestern Medical Center, working under the guidance of Dr. Thomas Kodadek, have developed a simple and inexpensive method for screening small synthetic molecules in order to identify potential drugs for the treatment of cancer and other diseases that are cheaper than existing drugs.
The active substances in many of the recently developed biological products are monoclonal antibodies that specifically bind to sites of strictly defined proteins, but their production is extremely expensive.
The results obtained by the authors indicate that the corresponding peptoids interact with target proteins with the same accuracy as antibodies, while having a much lower cost.
Peptoids are synthetic analogues of fragments of amino acid sequences of natural proteins (peptides), some of which are used as drugs – for example, insulin for diabetes replacement therapy or antibodies for the treatment of certain types of cancer. Most of these drugs have to be injected, because when taken orally, they are destroyed by the action of digestive enzymes. Peptoids resistant to these enzymes, on the contrary, can be taken in the form of tablets. Their production is much easier and cheaper than the production of antibodies. In addition, peptoid molecules are much smaller than antibody molecules, which may facilitate their penetration into tumor areas and tissues affected by various diseases.
The proposed method is simple and does not require large time and financial costs. It is designed to work with existing compounds and does not require complex devices, except for a flow fluorimeter, which is necessary for sorting molecules.
With its help, the authors tested about 300,000 peptides for their interaction with the receptor for vascular endothelial growth factor-2 (VEGFR2), which plays an important role in the formation of blood vessels. The process of interaction of this receptor with a signaling protein – vascular endothelial growth factor (VEGF) – is very important for the normal functioning of the body, but under certain conditions promotes the growth of tumors.
The new technology involves attaching hundreds of thousands of peptoid molecules to tiny plastic spheres. For screening, the authors marked VEGFR2–expressing cells with a red fluorescent marker, and those without this receptor with a green one. The particles loaded with peptoids were incubated with a mixture of labeled cells, after which the particles bound to the red-labeled cells were selected using an automated installation.
The whole procedure, during which scientists isolated 5 peptoids, took only a couple of days, which proved the ability of the proposed method to quickly and very effectively narrow the search area.
After that, the authors tested one of the five peptoids that binds most strongly to VEGFR2 and found that it blocks the activity of the receptor in cell culture. Small doses of this peptoid slowed down the growth of tumors and reduced the density of tumor vessels in mice with implanted human tumors of bone and soft tissues.
For the treatment of some types of cancer, commercial drugs based on antibodies are used that block the interaction of VEGF and its receptor and thus deprive the tumor of blood supply. However, the course of such therapy costs the patient about 20,000 US dollars
The authors believe that their proposed new method of rapid isolation of active peptoids will speed up the process of developing new drugs, the cost of which will be ten times lower than the cost of modern analogues.
Portal "Eternal youth" www.vechnayamolodost.ru based on materials from UT Southwestern Medical Center
14.04.2008