Miguel Machuqueiro, Principal Investigator at the Computational Biophysics Lab, at Ciências ULisboa, published a new paper, first-authored by Tomás Silva, former PhD student from the same lab, in the Journal of Chemical Information and Modeling by the American Chemical Society, on which the authors present a computational model they develop to design pH-low insertion peptides, smart delivery agents for cancer cells. 

What was the starting point that led to the current research?

pHLIP (pH-low insertion) peptides are smart delivery agents in the world of medicine. They have a special ability to sense and respond to acidity, like what you find in certain parts of our body, such as tumor cells. When they encounter an acidic environment, they change shape and attach to those areas. This unique feature makes them useful for targeting (they find the tumors) and delivering medications specifically to where they are needed, like a precision-guided missile for treating diseases.

What is the main finding reported in this paper?

In this work, in collaboration with the Andreev and Reshetnyak groups at Rhode Island Univ. (USA), we studied a series of pHLIP variants that were specifically designed to fine-tune this technology. The computational models built at the Computational Biophysics Lab helped interpret the experimental data and hopefully will provide valuable clues on how to improve this technology in the future.

If you had to explain the main finding to a 5-year-old child, how would you do it? 

We used computers to virtually design new pHLIP peptides, which are tiny molecules that can sneak into cancer cells, to deliver medicine and kill them.

Why is it important for the scientific community and for society at large?

pHLIP peptides have the potential to revolutionize drug delivery, making treatments more effective, less harmful, less prone to drug resistance, and potentially contributing to advancements in the field of medicine and healthcare.

What are the next steps?

Some of the findings from this work are currently being tested in the wet lab, both in our collaborators Lab (https://newton.uri.edu/biophysics/) and in the start-up company they have created (https://phlipinc.com). We will continue studying this system, since, as is common in science, there are always many open questions that need to be addressed.

Figure: Structural models of the different pHLIP variants with predictions of membrane-insertion pKa values and their respective experimental validation [paper’s graphical abstract]

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Read the full paper here.