📰 Discovery of a new source of potential drugs

© Sebastien Britton

Some marine sponges produce cytotoxic lipids from which synthetic analogues particularly toxic to cancer cells have been developed. However, their mechanism of action remained enigmatic. In works published in the journal eLifethe scientists reveal this mechanism and demonstrate that it represents a source of new molecules with selective cytotoxicity which could be used against the cancer (Cancer is a disease characterized by abnormal cell proliferation…)even against certain infectious diseases according to the same principle.

Many drugs have been inspired by natural molecules. Among the compounds isolated from marine organisms and presenting potential medicinal properties, lipids produced by marine sponges and characterized by an alkynylcarbinol function have long attracted attention for their cytotoxic properties. These natural molecules have inspired the chemical development of a large family of synthetic compounds that are highly toxic to tumor cells. However, the use therapeutic (Therapeutics (from the Greek therapeuein, to cure) is the part of medicine that…) of these molecules depended on the discovery of their mechanism of action.

To elucidate this mechanism, the scientists focused on the most active synthetic derivatives of this family, called dialkynylcarbinols, around 1000 times more toxic than the natural molecules that inspired them. They selected haploid human cells resistant to the cytotoxic effects of these molecules. In L’whole (In set theory, a set intuitively designates a collection…) resistant cells, they showed that the embarrassed (A gene is a deoxyribonucleic acid (DNA) sequence that specifies the…) HSD17B11 was inactivated by mutations. HSD17B11 is a enzyme (An enzyme is a molecule (protein or RNA in the case of ribozymes) allowing…) whose physiological function is the inactivation by oxidation of a steroid (Steroids are a group of lipids derived from triterpenoids…) endogenous.

By combining many approaches, scientists show that HSD17B11 oxide (An oxide is a compound of oxygen with a minus element…) the lipids studied in reactive forms which will immediately bind to several essential cellular proteins involved in the « control (The word control can have several meanings. It can be used as a synonym of examination, of…) quality of proteins ». This fixation blocks the processes associated and induced (The armature is a generally electromagnetic device used in electrical engineering responsible for…) very quickly the accumulation of incorrect proteins leading to the dead (Death is the final state of a biological organism that ceases to live (even if…) cellular. HSD17B11 is also required for the cytotoxicity of related molecules, including the natural molecules that inspired their development. These lipids are therefore pro-drugs bioactivated by a cellular enzyme into cytotoxic reactive species.

To better define their potential anticancer (An anticancer drug is a medicine used to fight cancer)the screening of a panel (The panel is a group of people who are regularly asked about their opinions or their…) of tumor lines was undertaken and made it possible to show that a rare pediatric cancer, osteosarcoma, is particularly sensitive to these molecules whereas they have no effect on cancer lines lacking HSD17B11.

HSD17B11 is just one protein (A protein is a biological macromolecule composed of one or more…) among a very large family of enzymes called Short-chain Dehydrogenases/Reductases (SDRs) which includes more than 500,000 representatives distributed in all living organisms. The researchers wanted to show that it was possible to design from their compounds new molecules capable of being selectively activated by other SDRs into cytotoxic compounds. For two other human SDRs, RDH11 and HPGD, they were able to develop new lipids whose cytotoxicity is based on their activate (Activation may refer to:) by these enzymes. This work therefore opens up the possibility of developing agents making it possible to selectively eliminate a cell or an organism expressing a specific SDR.

Thus, the natural or bio-inspired molecules of this family represent a source of potential drugs against various pathologies including cancer and infectious diseases. Researchers have already begun to exploit their results by developing promising new anti-cancer agents which they have patented.

Cellular enzymes, Short-chain Dehydrogenases/Reductases (SDRs), are able (1) to specifically convert natural and synthetic pro-cytotoxic lipids into reactive lipids. These activated lipids will (2) attach irreversibly to several essential cellular proteins involved in the « protein quality control » system, which notably makes it possible to ensure that proteins which have not been correctly folded are degraded by the proteasome to prevent them from disrupting the cell. Modifications of the proteins of this system by activated lipids lead to its inhibition which causes (4) the accumulation of incorrect proteins and rapidly leads to (5) cell death. © Sebastien Britton.

Reference:

Demange P., Joly E., Marcoux J., Zanon PRA, Listunov D., Rullière P., Barthes C., Noirot C., Izquierdo J.-B., Rozié A., Pradines K., Hee R., by Brito MV, Marcellin M., Greenhouse (A greenhouse is a generally closed structure intended for production…) RF, Bouchez O., Burlet-Schiltz O., Oliveira MCF, Ballereau S., Bernardes-Génisson V., Maraval V., Calsou P., Hacker SM, Génisson Y., Chauvin R^.Britton S.
SDR enzymes oxidize specific lipidic alkynylcarbinols into cytotoxic protein-reactive species
eLife May 10, 2022.
https://doi.org/10.7554/eLife.73913

contacts:
– Sebastien Britton – Searcher (A researcher (fem. researcher) refers to a person whose job is to do research…) CNRS (The National Center for Scientific Research, better known by its acronym CNRS, is the largest…) at theInstitute (An institute is a permanent organization created for a certain purpose. It is…) of pharmacology (Pharmacology is a scientific discipline of life, a subdivision of biology, which…) and biology (Biology, commonly called « bio », is the science of life….) structural (CNRS/Paul Sabatier University) –
sebastien.britton at ipbs.fr
– Stéphanie Younès – Manager Communication (Communication concerns both man (intra-psychic, interpersonal communication, etc.) – Institute of chemistry (Chemistry is a natural science divided into several specialties, to…) du CNRS – inc.communication at cnrs.fr
– Anne-Valérie Ruzette – Responsible scientific (A scientist is a person who is dedicated to the study of a science or sciences and who…) for communication – CNRS Institute of Chemistry – anne-valerie.ruzette at cnrs.fr
– Christophe Cartier says Mill (A mill is a machine for grinding cereal grains into flour and, by analogy,…) – Researcher at the Paris Institute of Molecular Chemistry & Project Manager for scientific communication at the INC
– inc.communication at cnrs.fr