Robert Lokey
University of California-Santa Cruz, CA·Chemistry
Many disease-relevant proteins are called "undruggable." They act through broad, flat contacts with partner proteins that ordinary small drugs cannot block, and they sit inside cells, where large molecules such as antibodies cannot reach. Ring-shaped peptide molecules called macrocyclic peptides sit in between: they can bind such targets with the strength and selectivity of an antibody, and some, especially natural products, also cross cell membranes on their own and can even be absorbed after being swallowed.
- Fields
Chemistry
Pharmacology
Biochemistry
- Topics
macrocyclic peptides
membrane permeability
passive diffusion
- Grants
- 1 known grant, through Dec 2027
What they work on
- Determine how far side chains can shield polar backbone atoms of a macrocyclic peptide inside a membrane, and conversely how much polar side-chain chemistry can be carried across by interacting with the backbone.
- Test whether particular macrocycle ring geometries enhance membrane permeability, and establish the fundamental upper size limit for passive permeability in the 700-1,500 molecular weight range.
- Determine how many strongly ionizable, charged groups can be built into fat-soluble macrocyclic peptides before passive membrane permeability is lost.
- Use DNA-encoded libraries of 10^8-10^12 macrocycles, where each molecule carries a DNA barcode, with chromatographic separation by permeability and next-generation sequencing to discover permeable scaffolds above 1,000 molecular weight.
- Measure how scaffold geometry affects efflux, the pumping of molecules back out of cells, and liver metabolism, using split-pool synthesis with tandem mass spectrometry readout.
More about the research
The open question is what molecular features allow molecules this large (molecular weight roughly 700 to 1,500) to pass passively through a membrane. The lab works on the basic physical and chemical rules behind that behavior, and has shown that known macrocyclic natural products represent only a small slice of the permeable shapes possible in this size range.
Why it matters
Reaching protein targets inside cells, particularly protein-protein interactions, is one of the central obstacles in drug discovery. Defining the rules that let membrane-permeable macrocyclic peptides enter cells, resist being pumped back out, and survive liver metabolism could give medicinal chemists a general platform for designing lead compounds against targets currently considered undruggable.
Known grants
From NIH and NSF research grants. Labs often have other funding we can't see.
Closest labs
Juan Hu
San Diego State University, CA·Chemistry·Early-career
Screen DNA-encoded combinatorial libraries, in which each compound carries an identifying DNA barcode, with a droplet-scale permeation assay to find cyclic peptides that efficiently cross membrane bilayers.
Mingxing Teng
Baylor College of Medicine, TX·Pharmacology
Build a comprehensive atlas of the cereblon interactome spanning canonical G-loop degron proteins, mutant G-loop variants and hidden non-G-loop targets, extending bioinformatic predictions already covering 2,458 candidate proteins.
Rovshan Sadygov
University of Texas Medical Branch at Galveston, TX·Biochemistry
Develop methods to estimate protein turnover from the deuterium labeling of fragment ions in tandem mass spectra, which are less distorted by space-charging, limited dynamic range and co-eluting contaminants than intact peptide ions.
The school
University of California-Santa Cruz: 15 labs on PI Pages, $218M a year on research, 183 research doctorates a year.
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