New cyclization reactions for synthesizing macrocyclic drug leads

August 21, 2019

Macrocyclic compounds are ring-shaped molecules made by connecting two ends of linear molecules. One of their unique and exciting properties is that their cyclical configuration reduces their flexibility, which means that macrocycles need less energy to bind targets than conventional small molecules.

In fact, macrocycles show a great ability to bind difficult targets that have flat, featureless surfaces. This has raised tremendous interest in the pharmaceutical industry, which is particularly interested in macrocyclic compounds with a molecular weight below 1 KDa, which would be small enough to cross the cell membrane and reach intracellular disease targets, e.g. proteins or even genes in the cell.

Still, there is a hurdle: there aren't enough suitable macrocycle libraries or methods to generate such small macrocycles. The compound libraries that pharmaceutical companies use today in high-throughput screens do contain 1-2 million different molecules, but those are mostly classical small molecules and only a handful are actual macrocyclics - at most, only a few hundred. This is too small a number for the screens to yield good hits when searching for possible drug candidates against challenging disease targets.

Now, scientists at EPFL have found a way to generate libraries of more than 9,000 of macrocyclic molecules below 1 KDa, all with high structural diversity. "Initially, what we wanted to do is generate orally available or cell-permeable macrocyclic drugs," says Professor Christian Heinis, whose lab led the study.

The libraries were generated by "cyclizing" short linear peptides in combination with diverse linker reagents, which promote chemical bonding. The yields of the macrocyclization reactions turned out to be so efficient that there was no need for purification. And in a key breakthrough, the new method also led to the discovery of surprisingly efficient macrocyclization reactions based on the ligation of thiol and amino groups of short peptides.

The work was supported by EPFL's Biomolecular Screening Facility (BSF), headed by Gerardo Turcatti. "EPFL has already developed the liquid handling processes to perform the combinatorial synthesis and to screen the macrocyclic compound libraries," he says. Screening identified binders of different disease targets, including inhibitors of thrombin, an important target of coagulation disorders. X-ray structure analysis of a thrombin inhibitor by partners in Italy showed a snug fit of the macrocycle to its target.

Heinis's lab is now further developing the macrocycle synthesis approach in order to screen even larger combinatorial libraries. Working closely with the BSF with the support of NCCR Chemical Biology, the next step is to generate macrocyclic inhibitors of intracellular protein-protein interactions, for which we currently have no good inhibitors.
-end-
Other contributors

University of Padova

Ca' Foscari University of Venice

Reference

S. S. Kale, M. Bergeron-Brlek, Y. Wu, M. G. Kumar, M. V. Pham, J. Bortoli, J. Vesin, X.-D. Kong, J. Franco Machado, K. Deyle, P. Gonschorek, G. Turcatti, L. Cendron, A. Angelini, C. Heinis. Thiol-to-amine cyclization reaction enables screening of large libraries of macrocyclic compounds and the generation of sub-kDa ligands. Science Advances 21 August 2019. DOI: 10.1126/sciadv.aaw2851

Ecole Polytechnique Fédérale de Lausanne

Related Science Articles from Brightsurf:

75 science societies urge the education department to base Title IX sexual harassment regulations on evidence and science
The American Educational Research Association (AERA) and the American Association for the Advancement of Science (AAAS) today led 75 scientific societies in submitting comments on the US Department of Education's proposed changes to Title IX regulations.

Science/Science Careers' survey ranks top biotech, biopharma, and pharma employers
The Science and Science Careers' 2018 annual Top Employers Survey polled employees in the biotechnology, biopharmaceutical, pharmaceutical, and related industries to determine the 20 best employers in these industries as well as their driving characteristics.

Science in the palm of your hand: How citizen science transforms passive learners
Citizen science projects can engage even children who previously were not interested in science.

Applied science may yield more translational research publications than basic science
While translational research can happen at any stage of the research process, a recent investigation of behavioral and social science research awards granted by the NIH between 2008 and 2014 revealed that applied science yielded a higher volume of translational research publications than basic science, according to a study published May 9, 2018 in the open-access journal PLOS ONE by Xueying Han from the Science and Technology Policy Institute, USA, and colleagues.

Prominent academics, including Salk's Thomas Albright, call for more science in forensic science
Six scientists who recently served on the National Commission on Forensic Science are calling on the scientific community at large to advocate for increased research and financial support of forensic science as well as the introduction of empirical testing requirements to ensure the validity of outcomes.

World Science Forum 2017 Jordan issues Science for Peace Declaration
On behalf of the coordinating organizations responsible for delivering the World Science Forum Jordan, the concluding Science for Peace Declaration issued at the Dead Sea represents a global call for action to science and society to build a future that promises greater equality, security and opportunity for all, and in which science plays an increasingly prominent role as an enabler of fair and sustainable development.

PETA science group promotes animal-free science at society of toxicology conference
The PETA International Science Consortium Ltd. is presenting two posters on animal-free methods for testing inhalation toxicity at the 56th annual Society of Toxicology (SOT) meeting March 12 to 16, 2017, in Baltimore, Maryland.

Citizen Science in the Digital Age: Rhetoric, Science and Public Engagement
James Wynn's timely investigation highlights scientific studies grounded in publicly gathered data and probes the rhetoric these studies employ.

Science/Science Careers' survey ranks top biotech, pharma, and biopharma employers
The Science and Science Careers' 2016 annual Top Employers Survey polled employees in the biotechnology, biopharmaceutical, pharmaceutical, and related industries to determine the 20 best employers in these industries as well as their driving characteristics.

Three natural science professors win TJ Park Science Fellowship
Professor Jung-Min Kee (Department of Chemistry, UNIST), Professor Kyudong Choi (Department of Mathematical Sciences, UNIST), and Professor Kwanpyo Kim (Department of Physics, UNIST) are the recipients of the Cheong-Am (TJ Park) Science Fellowship of the year 2016.

Read More: Science News and Science Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.