Cytoplasmic dyneins are motor proteins in the AAA+ superfamily that power transport of cellular cargos towards microtubule minus-ends. Recently, ciliobrevins were reported as selective cell-permeable inhibitors of cytoplasmic dyneins. As is often true for first-in-class inhibitors, the use of ciliobrevins has been limited by low potency. Moreover, suboptimal chemical properties, such as the potential to isomerize, have hindered efforts to improve ciliobrevins. Here, we characterized the structure of ciliobrevins and designed conformationally-constrained isosteres. We identified dynapyrazoles, inhibitors more potent than ciliobrevins in vitro, and find that while ciliobrevins inhibit both dynein's microtubule-stimulated and basal ATPase activity, dynapyrazoles block only microtubule-stimulated activity. Single-digit micromolar concentrations of dynapyrazoles block intraflagellar transport in the cilium and lysosome motility in the cytoplasm, processes that depend on cytoplasmic dyneins. Together, our studies suggest that chemical structure-based analyses can lead to inhibitors with distinct modes of inhibition and improved properties.
Pharmacology, Toxicology and Pharmaceutical Science
2
4%
Neuroscience
2
4%
Other
5
10%
Unknown
13
27%
Attention Score in Context
Attention Score in Context
This research output has an Altmetric Attention Score of 3. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 05 June 2017.
All research outputs
#15,860,146
of 26,850,401 outputs
Outputs from eLife
#13,376
of 16,561 outputs
Outputs of similar age
#171,810
of 332,045 outputs
Outputs of similar age from eLife
#293
of 365 outputs
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