SA question: Question: What advantages do you see
Post# of 154977
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Posted On: 09/18/2019 12:57:55 AM
SA question: Question: What advantages do you see for Pro-140 in head-to-head competition to an oral CCR-5 antagonist? Certainly, the Mariviroc has shown toxicity and a low BA, but perhaps another oral CCR-5 with less tox would eat Pro-140's lunch?
Besides the years it would take a new pill to be approved, small molecule Ccr5 antagonists have issues, all develop resistance, see the quote below. To switch to competitive like pro 140, injection is required I believe. Then you have the toxicity that small molecules give by blocking the natural Ccr5 activity. Pro 140 is like the perfect match, it blocks exactly where and what it needs and nothing more, in a manner that resistance is not created.
https://aac.asm.org/content/50/10/3289
Whereas the available small-molecule CCR5 inhibitors potently block the natural activity of CCR5 (11, 39, 40, 48), antiviral concentrations of PRO 140 do not block CCR5 function in vitro (33). In addition, preliminary studies indicate that PRO 140 is highly active against viruses that are resistant to small-molecule CCR5 antagonists (20, 27). These functional differences are likely related to the distinct differences in CCR5 binding. Small-molecule CCR5 antagonists bind a hydrophobic pocket formed by the transmembrane helices of CCR5 and inhibit HIV-1 via allosteric mechanisms (13, 30, 47, 48), while PRO 140 binds an extracellular epitope on CCR5 and appears to act as a competitive inhibitor (33).
Besides the years it would take a new pill to be approved, small molecule Ccr5 antagonists have issues, all develop resistance, see the quote below. To switch to competitive like pro 140, injection is required I believe. Then you have the toxicity that small molecules give by blocking the natural Ccr5 activity. Pro 140 is like the perfect match, it blocks exactly where and what it needs and nothing more, in a manner that resistance is not created.
https://aac.asm.org/content/50/10/3289
Whereas the available small-molecule CCR5 inhibitors potently block the natural activity of CCR5 (11, 39, 40, 48), antiviral concentrations of PRO 140 do not block CCR5 function in vitro (33). In addition, preliminary studies indicate that PRO 140 is highly active against viruses that are resistant to small-molecule CCR5 antagonists (20, 27). These functional differences are likely related to the distinct differences in CCR5 binding. Small-molecule CCR5 antagonists bind a hydrophobic pocket formed by the transmembrane helices of CCR5 and inhibit HIV-1 via allosteric mechanisms (13, 30, 47, 48), while PRO 140 binds an extracellular epitope on CCR5 and appears to act as a competitive inhibitor (33).
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