Discovering new drugs with Darwin

Our body must constantly defend itself against bacteria and viruses. It generates millions of different antibodies, which are selected to recognise the enemy and trigger the best possible immune response. Scientists use these antibodies to for therapeutic purposes to target proteins and disrupt their harmful. However, identifying the small molecules that will form the basis of the drug is a long and tedious process. Chemists at the University of Geneva (UNIGE), Switzerland, have developed a technique inspired by the theory of Darwinian evolution: amplifying the best combinations and generating diversity allows biology to find solutions to new problems. They have created a new methodology that rapidly generates millions of combinations of small molecules through programmed assembly using DNA-pairing processes, finding the best possible combination to counter a target protein within two weeks. These results, published in the journal Nature Chemistry, will open up a new and untapped space for drug development.

The way drugs work is based on the molecular recognition of a target protein involved in the disease, in order to disarm it. To do this, scientists use high-throughput screening to identify which molecule could become a drug, specifically targeting the protein of interest. Over the last ten years, the technique has been improved by encoding small molecules with DNA tags that simplify their identification, as DNA is easy to decode.

Drawing inspiration from Darwinian evolutionary forces to find efficient assemblies

Today, chemists at the UNIGE have gone one step further, drawing inspiration from Darwin's theories: "Biology always finds a solution to a problem, explains Nicolas Winssinger, professor in the Department of Organic Chemistry at the Faculty of Science, UNIGE, and the corresponding author of the study. This is the principle of natural evolution, which consists of amplifying the best individuals, while generating diversity to adapt and survive changing conditions. That's what we’ve set up for small molecules." Indeed, the scientists have developed a technology that generates diversity by creating more than 100 million assemblies of molecules via their DNA, which they then select to best match a particular protein.

"We were inspired by the characteristics of antibodies that recognise target proteins and sought to mimic them in the form of simpler molecules to allow them to be assembled in different combinations, directed by DNA sequences," explains Nicolas Winssinger. These combinations are then selected and amplified several times to find the best possible match with the protein to be targeted, all in one to two weeks, compared with months or even a year for traditional high-throughput screening.

A proven, easily reproducible and inexpensive technique

To validate the effectiveness of this methodology, the Geneva team focused on the PD-L1 protein, which protects cancer cells by diverting the immune system. "Thanks to our methodology, we quickly identified an assembly that specifically targets PD-L1, confirming that it works effectively," says Nicolas Winssinger.

This technique, which is easy to reproduce in any laboratory in the world, costs only a few thousand francs, compared with millions for high-throughput screening."By exploiting the evolutionary forces highlighted by Darwin, we can now improve our molecular assemblies and open up a new space of possible combinations that has not yet been exploited, in order to create new, more effective drugs," concludes the Geneva researcher.

Vummidi BR, Farrera-Soler L, Daguer JP, Dockerill M, Barluenga S, Winssinger N.
A mating mechanism to generate diversity for the Darwinian selection of DNA-encoded synthetic molecules.
Nat Chem. 2021 Dec 6. doi: 10.1038/s41557-021-00829-5

Most Popular Now

Positive Phase 1 data from mRNA-based individualiz…

BioNTech SE (Nasdaq: BNTX, "BioNTech") announced initial data from an ongoing investigator-initiated first-in-human Phase 1 study evaluating the safety and tolerability o...

FDA approves RIABNI™ (rituximab-arrx), a biosimila…

Amgen (NASDAQ:AMGN) today announced that the U.S. Food and Drug Administration (FDA) has approved RIABNI™ (rituximab-arrx), a biosimilar to Rituxan®, in combination with ...

Pfizer to invest $120 million to produce COVID-19 …

Pfizer Inc. (NYSE: PFE) announced today that it will further strengthen its commitment to United States manufacturing with a $120 million investment at its Kalamazoo, Mic...

Proteomic study of 2,002 tumors identifies 11 pan-…

A new study that analyzed protein levels in 2,002 primary tumors from 14 tissue-based cancer types identified 11 distinct molecular subtypes, providing systematic knowled...

A new technology offers treatment for HIV infectio…

A new study from Tel Aviv University offers a new and unique treatment for AIDS which may be developed into a vaccine or a one time treatment for patients with HIV. The s...

Sanoff offers perspective on a promising rectal ca…

UNC Lineberger Comprehensive Cancer Center's Hanna K. Sanoff, MD, MPH, is the author of a viewpoint in the New England Journal of Medicine that provides a perspective on ...

Boehringer Ingelheim signs option to acquire Truti…

Boehringer Ingelheim announced the signing of an option to acquire Trutino Biosciences Inc. (the "Transaction"), a San Diego-based biotech company. Trutino Biosciences...

Broadly neutralizing antibodies could provide immu…

Two broadly neutralizing antibodies show great promise to provide long-acting immunity against COVID-19 in immunocompromised populations according to a paper published Ju...

Novel drug combo activates natural killer cell imm…

Most skin cancer drugs that activate the immune system work by triggering immune cells, called T cells, to attack tumors, but when T cells are activated for too long, the...

Novartis announces Nature Medicine publication of …

Novartis announced that Nature Medicine published final results from both the two- and three-copy cohorts of the completed Phase 3 SPR1NT trial as separate companion manu...

COVID-19 rebound after taking Paxlovid likely due …

Paxlovid is the leading oral medication for preventing severe cases of COVID-19 in high-risk individuals. However, symptoms returned in some patients after treatment was ...

Biomarkers found that could be drug targets agains…

Biomarkers that could be targets for novel drugs to treat glioblastoma brain tumors have been identified by investigators at Georgetown Lombardi Comprehensive Cancer Cent...