By: Kyra Ezikeuzor
Scientists at the Arc Institute, an institution for biomedical science and technology located in Palo Alto, California, and the University of California at San Francisco have discovered findings that may establish new possibilities for a key challenge in drug discovery. That challenge is the tradeoff between a drug’s ability to travel across the cell membrane to its target and its eventual ability to fit into its target. A new study published by Kevan Shokat at University of California at San Francisco and Luke Gilbert at the Arc Institute has reported a novel discovery of an important pathway for larger drug molecules to reach their targets. This finding is significant because it can be used to develop new drugs that despite being large and complex for binding optimally with their targets, can still be effectively taken up by their target cells.
The majority of traditional pharmaceuticals are small drug molecules that follow simple methods for optimal cellular uptake. These drugs typically have limits on their molecular size and the number of chemical groups that can be bound to their surfaces. However, many targets for these drugs such as kinase enzymes which are often involved in cancers are very difficult to target with traditional drugs because there are issues with specificity. According to the first author of the Science study, Kevin Lou, “there are over 500 human kinase enzymes that are so similar in the pocket where the drug binds, making it a difficult challenge to selectively target a single member of this family, […] leading to undesirable medication side effects.”
To combat these issues with specificity, newer varieties of drugs have been made to be larger and more complex. According to Gilbert, it is unclear how scientists can design and develop new drugs to achieve high specificity to match their targets and make them able to reach their targets in the first place. However, scientists are discovering new pathways to combat this complication. Scientists have tested large drug molecules using the interferon-induced transmembrane (IFITM) pathways to enter cells in regions outside of the traditional and typical drug design constraints, a process which opens up a significant number of opportunities for scientists to discover new possibilities for larger and more specific drug molecules using the IFITM pathway.
Scientists in the study continued searching for new pathways for larger and more specific drugs by conducting genome functional screens, tests which examine the individual importance of genes on processes in the cell. Gilbert had previously led the development of the CRISPRi and CRISPRa screens. These tests used CRISPR machinery with an RNA library to allow for the selective altering of the expression levels of one gene at a time across the entire human genome. Eventually, Shokat and Gilbert’s team conducted these screens in human leukemia cells with the anti-cancer drug treatment RapaLink-1. Quickly, the scientists observed that RapaLink-1 directly and specifically responded to various genetic manipulations the scientists administered. This is an important finding because it proved RapaLink-1 to be dependent on alternate pathways for entry into its cellular targets and alternate drug action to compared to typical small drug molecules and pharmaceuticals.
Overall, Shokat’s and Gilbert’s work at UCSF and Arc Institute has opened up new possibilities for making more effective, specific, and complex drugs. Because of their research, scientists can now understand and utilize a new, important cellular pathway through which drugs can enter human cells, paving the path forward for more efficient molecular drug design.
Citations
Lou, Kevin, et al. “IFITM Proteins Assist Cellular Uptake of Diverse Linked Chemotypes.” Science, vol. 378, no. 6624, 8 Dec. 2022, pp. 1097–1104, https://doi.org/10.1126/science.abl5829.
Pawluk, April. “How Big, Bulky Drugs Get into Our Cells | Arc Institute.” Arcinstitute.org, 8 Dec. 2022, arcinstitute.org/news/blog/cellular-uptake-pathway.
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