Despite high cytotoxic activity towards some cancer cells, the mechanism of action of a large family of synthetic compounds inspired by natural small molecules produced by some marine sponges was lacking. A study published in eLife reveals that these molecules are prodrugs bioactivated by an enzyme of the Short-Chain Dehydrogenase/Reductase (SDR) superfamily into protein-reactive species. These species covalently attach to a set of essential proteins resulting in rapid cell death. Based on this mechanism, the scientists also demonstrated that it is possible to develop novel pro-cytotoxic lipids selectively bioactivable by other SDRs, opening new prospects in term of drug discovery.
Multiple drugs are inspired by natural small molecules. Among marine compounds with potential medicinal properties, lipidic molecules produced by some marine sponges and characterized by a chiral alkynylcarbinol function have been identified as potent cytotoxic molecules on cancer cells. Inspired by these molecules, chemistry teams in Toulouse designed a large family of synthetic analogues with an optimized cytotoxic activity towards some cancer cells. However the mechanism of action of these molecules was elusive, limiting their potential therapeutic use.
In order to decipher this mechanism, scientists focused on one of the most potent series, the dialkynylcarbinols, around 1000 times more toxic than some of the related natural molecules. They first isolated from chemically mutagenized human haploid cells a set of clones that were highly resistant to the cytotoxicity of these molecules. Identification of the mutations in these clones through next-generation sequencing revealed that they are all localized in a gene coding for the HSD17B11 protein. HSD17B11 is a Short-chain Dehydrogenase/Reductase (SDR) described as inactivating a specific androgen through NAD+-dependent oxidation.
Through multiple experiments, the team then revealed that HSD17B11 enantiospecifically oxidizes dialkynlcarbinols into dialkynylketones, that they identified as potent protein-reactive electrophiles. These species modify a set of proteins involved in Protein Quality Control mechanisms, which describes multiple systems that help complex proteins to fold properly and degrade them when they fail to. Modification by these reactive lipids, a process called lipoxidation, leads for some proteins to their reassociation to cellular membranes and overall inactivates the quality control mechanisms leading to a lethal proteotoxic stress resulting from the accumulation of unfolded proteins. Importantly, HSD17B11 was also required for the cytotoxicity of all the related molecules, including the natural lipids that inspired their development, indicating that these compounds are all HSD17B11-bioactivated prodrugs.
HSD17B11 is only one protein of the large SDR superfamily that has more than 500,000 known representatives distributed in all living organisms. Based on the identified mechanism, the team developed novel prodrugs that are selectively bioactivated by the other human SDRs, RDH11 and HPGD. This opens the prospects of killing selectively cells or organisms that express a specific SDR. For example, HSD17B11 is highly expressed in some cancer cells and, by screening a panel of cancer cell lines, the team could demonstrate that HSD17B11-bioactivated compounds are highly toxic towards cancer cells from a rare pediatric cancer, osterosarcoma.
Cellular enzymes of the Short-chain Dehydrogenase/Reductase (SDR) superfamily are able to (1) specifically oxidize natural or artificial pro-cytotoxic lipids into protein-reactive species. These activated lipids (2) covalently attach to multiple essential proteins involved in Protein Quality Control (PQC) mechanisms. The modification, called lipoxidation, of these proteins (3) blocks the PQC mechanisms, including the ubiquitin-proteasome system, resulting (4) in the accumulation of unfolded proteins. The resulting proteotoxic stress induces (5) apoptotic cell death. ©Sébastien Britton
“SDR enzymes oxidize specific lipidic alkynylcarbinols into cytotoxic protein-reactive species”
Demange P#, Joly E#, Marcoux J#, Zanon PRA, Listunov D, Rullière P, Barthes C, Noirot C, Izquierdo JB, Rozié A, Pradines K, Hee R, de Brito MV, Marcellin M, Serre 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*
Elife May 10, 2022 - DOI: 10.7554/eLife.73913
Sébastien Britton | Sebastien.Britton@ipbs.fr | +33 (0)5 61 17 59 07 | @SebBritton1
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