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Posted On: 07/24/2021 9:46:41 AM
Post# of 148902
Some thoughts on the advantage of Leronlimab over maraviroc.
‘CCR5 adopts three homodimeric conformations that control cell surface delivery’
“ We provide evidence of three distinct CCR5 dimeric organizations, involving residues of transmembrane helix 5. Two dimeric states corresponded to unliganded receptors, whereas the binding of the inverse agonist maraviroc stabilized a third state. We found that CCR5 dimerization was required for targeting the receptor to the plasma membrane. ”
Maraviroc (intercellular binding of ccr5, rather than extracellular loop 2 and n-terminus) binding to ccr5 apparently stabilizes CCR5 as an intercellular monomer, preventing its activity at the cell surface.
This, it appears will block the constitutive activity of the associated G protein.
In this way, maraviroc seems to directly mirror delta-32, including the increased mortality that keeps the incidence of that allele lower than one would expect were delta-32 to not have a cost of reduced fitness.
Leronlimab may be a double winner, blocking HIV fusion and entry, but unlike delta-32, allowing a constitutively functional ccr5.
This may be well known to everyone else, but a bit of an epiphany for me.
This could certainly be the basis, beyond hepatotoxicity, for the advantage of Leronlimab over small molecule antagonists.
I had previously just been thinking about association with CCR5, forgetting that its cell surface expression is variable and dynamic
https://stke.sciencemag.org/content/11/529/eaal2869.full
‘CCR5 adopts three homodimeric conformations that control cell surface delivery’
“ We provide evidence of three distinct CCR5 dimeric organizations, involving residues of transmembrane helix 5. Two dimeric states corresponded to unliganded receptors, whereas the binding of the inverse agonist maraviroc stabilized a third state. We found that CCR5 dimerization was required for targeting the receptor to the plasma membrane. ”
Maraviroc (intercellular binding of ccr5, rather than extracellular loop 2 and n-terminus) binding to ccr5 apparently stabilizes CCR5 as an intercellular monomer, preventing its activity at the cell surface.
This, it appears will block the constitutive activity of the associated G protein.
In this way, maraviroc seems to directly mirror delta-32, including the increased mortality that keeps the incidence of that allele lower than one would expect were delta-32 to not have a cost of reduced fitness.
Leronlimab may be a double winner, blocking HIV fusion and entry, but unlike delta-32, allowing a constitutively functional ccr5.
This may be well known to everyone else, but a bit of an epiphany for me.
This could certainly be the basis, beyond hepatotoxicity, for the advantage of Leronlimab over small molecule antagonists.
I had previously just been thinking about association with CCR5, forgetting that its cell surface expression is variable and dynamic
https://stke.sciencemag.org/content/11/529/eaal2869.full
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