Lauren Slosky
@laurenslosky.bsky.social
Neuropharmacologist | Assistant Prof at the University of Minnesota | New PI interested in GPCRs, addiction biology & drug discovery | 🔬 ➡️ 🐭
Thank you Nina!!
October 27, 2025 at 10:12 PM
Thank you Nina!!
Thank you, Tom!!
October 27, 2025 at 9:24 PM
Thank you, Tom!!
Yay! Really psyched for the team here. Thank you, Zoe!!
October 27, 2025 at 9:23 PM
Yay! Really psyched for the team here. Thank you, Zoe!!
Led by superstar students @kelseyperson.bsky.social and Maddi Moore with @valeriarobleto.bsky.social. This entire line of investigation was made possible by Steve Olson and his med chem group @sbpdiscovery.bsky.social. Hugely grateful to our entire team at UMN and beyond!
October 27, 2025 at 8:50 PM
Led by superstar students @kelseyperson.bsky.social and Maddi Moore with @valeriarobleto.bsky.social. This entire line of investigation was made possible by Steve Olson and his med chem group @sbpdiscovery.bsky.social. Hugely grateful to our entire team at UMN and beyond!
Why are we excited? This is a strategy for changing the cellular consequences of receptor activation and achieving truly biased, G protein-subtype-selective compounds that is broadly applicable to the GPCR superfamily. So many new possibilities!
October 27, 2025 at 8:50 PM
Why are we excited? This is a strategy for changing the cellular consequences of receptor activation and achieving truly biased, G protein-subtype-selective compounds that is broadly applicable to the GPCR superfamily. So many new possibilities!
These data suggest that G protein selectivity can be tailored with small changes to a single chemical scaffold targeting the GPCR-transducer interface.
October 27, 2025 at 8:50 PM
These data suggest that G protein selectivity can be tailored with small changes to a single chemical scaffold targeting the GPCR-transducer interface.
Differences in the G protein selectivity profiles of these new modulators were probe-independent, conserved across receptor species, and translated to differences in in vivo activity - efficacy in a rodent model of NTSR1 agonist-induced hypothermia.
October 27, 2025 at 8:50 PM
Differences in the G protein selectivity profiles of these new modulators were probe-independent, conserved across receptor species, and translated to differences in in vivo activity - efficacy in a rodent model of NTSR1 agonist-induced hypothermia.
Other compounds produced surprising results indicating that some G protein C-termini can also adopt a third, distinct conformation in the presence of a stabilizing modulator. WHAT. 🤯
October 27, 2025 at 8:50 PM
Other compounds produced surprising results indicating that some G protein C-termini can also adopt a third, distinct conformation in the presence of a stabilizing modulator. WHAT. 🤯
Remarkably, small modifications to the SBI-553 scaffold produce compounds with qualitatively different G protein activation profiles! Some compounds behaved as predicted – like this one 🎳
October 27, 2025 at 8:50 PM
Remarkably, small modifications to the SBI-553 scaffold produce compounds with qualitatively different G protein activation profiles! Some compounds behaved as predicted – like this one 🎳
Can this compound’s G protein selectivity profile be changed by modifying its structure? Yes! Based on these models, we compiled a series of SBI-553 derivatives and screened them in a high-dimensional SAR study including representative G protein family members and β-arrestin.
October 27, 2025 at 8:50 PM
Can this compound’s G protein selectivity profile be changed by modifying its structure? Yes! Based on these models, we compiled a series of SBI-553 derivatives and screened them in a high-dimensional SAR study including representative G protein family members and β-arrestin.
G protein homology models based on this alternative, shallow-binding conformation did a great job at explaining SBI-553’s G protein subtype-specific effects on NT and its own agonism.
October 27, 2025 at 8:50 PM
G protein homology models based on this alternative, shallow-binding conformation did a great job at explaining SBI-553’s G protein subtype-specific effects on NT and its own agonism.
Why does this work? The G protein C-terminus needs to adopt a new binding position to accommodate the compound. SBI-553 blocks G protein binding determinants, promoting association with select G protein subtypes for which a shallow-binding conformation is energetically favorable.
October 27, 2025 at 8:50 PM
Why does this work? The G protein C-terminus needs to adopt a new binding position to accommodate the compound. SBI-553 blocks G protein binding determinants, promoting association with select G protein subtypes for which a shallow-binding conformation is energetically favorable.
If not through β-arrestin, where does the block come from? Subtype-selective steric exclusion. Sensitivity to SBI-553 antagonism is determined by the primary structure of the G protein C-terminus and can be changed by swapping just the 5 C-term amino acids of these G proteins.
October 27, 2025 at 8:50 PM
If not through β-arrestin, where does the block come from? Subtype-selective steric exclusion. Sensitivity to SBI-553 antagonism is determined by the primary structure of the G protein C-terminus and can be changed by swapping just the 5 C-term amino acids of these G proteins.
How does it do this? SBI-553 selectively fully antagonizes NTSR1-Gq/11 coupling. No β-arrestin needed for its G protein antagonism!
October 27, 2025 at 8:50 PM
How does it do this? SBI-553 selectively fully antagonizes NTSR1-Gq/11 coupling. No β-arrestin needed for its G protein antagonism!
This biased allosteric modulator (BAM) biases NTSR1 not only toward β-arrestin, but also toward alternative G protein signaling, switching NTSR1 from a Gq/11 preferring receptor to a G12/13 preferring receptor.
Pretty cool 🧪🧠🟦
Pretty cool 🧪🧠🟦
October 27, 2025 at 8:50 PM
This biased allosteric modulator (BAM) biases NTSR1 not only toward β-arrestin, but also toward alternative G protein signaling, switching NTSR1 from a Gq/11 preferring receptor to a G12/13 preferring receptor.
Pretty cool 🧪🧠🟦
Pretty cool 🧪🧠🟦
When NT and SBI-553 are applied in combination, SBI-553 antagonizes NT-induced activation of some G proteins and promotes NT-induced activation of others. Some strikingly transducer-specific effects here!
October 27, 2025 at 8:50 PM
When NT and SBI-553 are applied in combination, SBI-553 antagonizes NT-induced activation of some G proteins and promotes NT-induced activation of others. Some strikingly transducer-specific effects here!
Interestingly, we found that SBI-553 acts not only as a full β-arrestin agonist at NTSR1 but also a weak G protein agonist for a subset of G proteins (e.g., G12/13, Go).
October 27, 2025 at 8:50 PM
Interestingly, we found that SBI-553 acts not only as a full β-arrestin agonist at NTSR1 but also a weak G protein agonist for a subset of G proteins (e.g., G12/13, Go).