A fast-flowing robotic tool that can synthesize peptide nucleic acids in a single shot

Tiny Tides are set on a table. Credit: MIT

Researchers in the lab of Bradley Bentlot, professor of chemistry at MIT, have created a fully automated, fast-flowing tool that can synthesize peptide nucleic acids in a single shot.

By automating the synthesis of CPP-peptide-coupled nucleic acids (PPNAs) using a robot that the research team dubbed “Tiny Tides,” the typical PPNA synthesis time was reduced from several days to just two hours.

“This efficient new technology represents a potentially significant step forward to enable rapid on-demand production of a candidate antiallergic oligonucleotide, not only for COVID-19 but also for other diseases and emerging pathogens,” says Chengxi Li, a co-author on the research paper. and Postdoctoral Research Fellow in the Pentelute Group.

The research paper, “The Mechanistic Synthesis of Flux from Peptide−PNA Conjugates,” was recently published in ACS Central Science.

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PNAs are synthetic DNA-like molecules with a wide range of chemical and biological applications, and have emerged as a class of therapies used to treat various diseases from cancer to viral infections. Barriers to PNAs becoming medicated include low solubility, poor cellular uptake, and rapid elimination.

Some of these challenges have been addressed by the covalent binding of cell-penetrating peptides (CPP) to the PNA. However, CPP-conjugated PPNAs can be cytotoxic and often require time-consuming structural studies to reduce toxicity while improving delivery. In addition, although standard batch protocols allow efficient access to PNA sequences of less than 15 bases, longer sequences are challenging to synthesise and face limitations that can lead to low yields.

“Let the robot do it”

Designed by the Pentelute Group to replace the traditional stepwise installation via tap chemistry, the automatic fast flow device consists of seven units including a central control computer, a solution storage system, three HPLC pumps, three multi-position valves, heating elements, a reaction area, and UV-vis detector – all controlled by a standard script in the Mechwolf programming environment.

The research team decided to name it Tiny Tides for two reasons: their robot makes peptides or oligonucleotides, a small-volume compound capable of rapidly optimizing the state and synthesising using a low amount of reagent and solvent, a relatively small cost.

Despite the nickname, the performance is little. In lab tests, Tiny Tides reported 10 seconds per amide bond formation between PNA monomers—compared to 10 minutes per amide bond formation for microwave peptide compounds. or 32 min per conjugation cycle as with DNA Expedite 8909 complex encapsulated at room temperature. The variable temperature design of the Tiny Tides also eliminates the need for a temperature cap, while increasing coupling efficiency.

This production strategy is convenient for the simultaneous investigation of the bioactivity, toxicity and intracellular uptake of several PNAs. In addition, the speed and automation of this device allow for high-throughput investigation of many candidates to find the most effective PNA sequences for a target, with greatly improved speeds compared to current and commercial methods.

fight covid-19

While breakthroughs in vaccinology have taken center stage in the global COVID-19 pandemic, direct-acting antiviral agents could be another tool to eradicate this virus. In the laboratory, PNAs have been shown to be effective against SARS-CoV. The high sequence similarity with SARS-CoV-2, the virus that causes COVID-19, has led researchers to believe that antiperspirants PNAs may be a way to achieve SARS-CoV-2 inhibition.

Speed ​​and efficiency in the synthesis of PPNAs is a much-needed step toward being able to assess the many possible sequences for feasibility in treating disease. In this study, the Pentelute group chemically synthesized eight PPNAs to combat COVID-19 in just one day — a feat that would have taken about a month if it had been made by hand at a rate of two per week using previous methods.

Of the eight, one sequence eliminated more than 95 percent of the virus in the live infection assay.

New technology enables rapid protein synthesis

more information:
Chengxi Li et al, Automated Flow Synthesis of Peptide-PNA Comparisons, ACS Central Science (2021). DOI: 10.1021 / acscentsci.1c01019

Provided by the Massachusetts Institute of Technology

This story has been republished with permission from MIT News (web.mit.edu/newsoffice/), a popular site covering news about MIT research, innovation, and teaching.

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