A team of American researchers has managed to design a new protein ligand which, depending on the modifications applied to it, is capable of regenerating neuronal cells or inhibiting the growth of lung tumors. In other words, they created a “super-ligand” capable of healing the organism …
Our entire body is made up of cells. The different biological processes that regulate our health rely on various messengers, ligands, which bind to receptors on the surface of cells. But when the messages get confused, the body can get sick …
Changes That Affect Cellular Messages
Ligands – which can be small molecules, ions or proteins – are substances that can form a complex with a molecule in the body, for biological purposes. Typically, during a protein-ligand bond, the latter sends a signal when it binds to the receptor for the target protein; most of the time, the latter then changes conformation (its orientation and three-dimensional shape).
In her lab, Stanford University bioengineer Jennifer Cochran is studying how ligands and cellular receptors combine to transmit messages to cells. Above all, his team seeks to understand how to manipulate these interactions, so as to be able to create powerful therapeutic agents. ” These proteins can hopefully be used one day to treat neurodegenerative diseases, as well as cancers and other disorders such as osteoporosis and atherosclerosis “Said the specialist.
To this end, the Cochran team set out to modify a ligand so as to bring about specific modifications at the level of cells. Their results were the subject of an article in the journal Proceedings of the National Academy of Sciences. They thus carried out a series of experiments on rat and human cells, then on sick mice, in order to observe how their ligand could contribute to the healing of vital organs.
How did they do it? Like all proteins, ligands and receptors are made up of many different amino acids, linked together like a pearl necklace, and folded into various distinct three-dimensional shapes. Everyone must then find the right shoe: only the ligand with the right shape can adapt to the corresponding receiver, as there is only one key for each lock.
However, via molecular engineering techniques, researchers can modify the series of amino acids that make up the ligand; in this way, they create millions of different ligands, and then analyze their interactions with different receptors. The ligand that adapts perfectly and more effectively to a particular receptor – a kind of “super ligand”, called “superagonist” by scientists – could thus transmit messages to cells in a more efficient, more robust way.
Conversely, manipulation can make it possible to transform ligands into “antagonists”, in other words, keys corresponding well to the lock of the receiver, but capable of blocking the signal emitted (which would make it possible, for example, to delay a particular function, such than cell growth). The technique has largely inspired Cochran in his research for a new cancer therapy.
A regenerating and anti-cancer ligand!
Cochran already published an article on the subject last year, in collaboration with Alejandro Sweet-Cordero, cancer specialist at UC San Francisco. Their study revealed how a modified version of a receptor protein (CNTFR) had blocked the growth of lung tumors in mice. Long before that, in 2014, she also developed an experimental protein therapy, with Amato Giaccia, to treat metastatic cancers: their therapy consisted in stopping the development of metastases by preventing two proteins from initiating the spread of cancer.
The expert and her team built on this previous research to develop a superagonist ligand, called CLCF1, capable of binding to the CNTFR receptor. Introduced into a tissue culture of damaged neuronal cells, it turns out that this ligand has amplified the messenger signals promoting the growth of axons (the long fibers that carry nerve impulses), as if it were helping the failing neurons to regenerate!
Another very encouraging result: via a few additional modifications in the amino acids of CLCF1, the team showed that this ligand became a powerful antagonist capable of inhibiting the growth of lung tumors in mice. Two variants of the same molecule thus presented two major therapeutic interests!
On the same topic: Discovery of a “switch” to reverse and deactivate the growth and metastases of breast cancer
Jennifer Cochran has been interested in modified protein therapy for several years. ” I have long been fascinated by how proteins function as molecular machines in nature and how engineering tools allow us to shape the structure and function of proteins with the creativity of an artist “, She confides.
The technique could indeed be of great use in oncology and regenerative medicine. Several of his discoveries have led to preclinical developments; Trials in humans, linked to a potential treatment for ovarian and kidney cancer, are underway. In the meantime, this new study has confirmed that the modified ligands and receptors constitute a promising avenue for combating certain diseases.
Source: PNAS, Jun W. Kim el al.
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