An excellent analysis and I’m almost sure your mistrust in the pharmaceutical efficacy of Cerebrolysin is well founded. However, having some experience working in the field of brain-penetrant drugs, I can comment that your restrictions on molecular weight and properties are too conservative. Small molecules of >550 dalton are capable of crossing the blood brain barrier if very well tailored. Also small cyclic peptides can hide their polar backbones within buried intramolecular hydrogen bond networks and become membrane permeable. The bicyclic peptide SFTI-1, a 14mer peptide, has been shown brain penetrant in rat in what looks to me a reasonable study. So, playing devil’s advocate, there is a hypothesis that the lysis procedure generates certain cyclic peptides of 500-1000 Dalton that could penetrate the BBB and have a biological effect.
I don’t believe this hypothesis but it does need to be discounted. Such cyclic peptides should be straight-forward to detect by HPLC/MS, I’d have thought, through their significantly less polar nature. Has anyone published work looking for these in Cerebrolysin?
Thank you for this additional information! I had not heard of cyclic peptides. To my knowledge, no one has intentionally looked for cyclic peptides in cerebrolysin. However, I think it’s pretty unlikely. From what I read about cyclic peptides, they are either derived from natural sources (SFTI-1) or they are synthesized (as in this paper). Synthesizing cyclic peptides involves multiple steps just to get everything to fold correctly. So, it seems unlikely that the random cleavage of brain proteins that occurs in Cerebrolysin synthesis would yield any cyclic peptides.
Yes, I agree, I think it is pretty unlikely. But not completely impossible. As I said it should be pretty easy to find them if they are in the lysate via, HP liquid chromatography. Brain penetrant cyclic peptides should on the whole be significantly less polar than acyclic polypeptides of similar mass.
I’ve never heard of cyclic peptides. But I suppose it is possible.
Actually the HPLC study we cite talks about a similar possibility—they say the observed effects may be due to “cryptic peptides”, perhaps created by the lysing of larger proteins and peptides. It just seems very unlikely to me. To me, based on my metascience research, it’s a it easier to believe that the published literature is just plain wrong. Check out the HPLC paper—it’s he only we found doing that sort of analysis but it’s very detailed (https://analyticalsciencejournals.onlinelibrary.wiley.com/doi/abs/10.1002/dta.1817).
An excellent analysis and I’m almost sure your mistrust in the pharmaceutical efficacy of Cerebrolysin is well founded. However, having some experience working in the field of brain-penetrant drugs, I can comment that your restrictions on molecular weight and properties are too conservative. Small molecules of >550 dalton are capable of crossing the blood brain barrier if very well tailored. Also small cyclic peptides can hide their polar backbones within buried intramolecular hydrogen bond networks and become membrane permeable. The bicyclic peptide SFTI-1, a 14mer peptide, has been shown brain penetrant in rat in what looks to me a reasonable study. So, playing devil’s advocate, there is a hypothesis that the lysis procedure generates certain cyclic peptides of 500-1000 Dalton that could penetrate the BBB and have a biological effect.
I don’t believe this hypothesis but it does need to be discounted. Such cyclic peptides should be straight-forward to detect by HPLC/MS, I’d have thought, through their significantly less polar nature. Has anyone published work looking for these in Cerebrolysin?
Thank you for this additional information! I had not heard of cyclic peptides. To my knowledge, no one has intentionally looked for cyclic peptides in cerebrolysin. However, I think it’s pretty unlikely. From what I read about cyclic peptides, they are either derived from natural sources (SFTI-1) or they are synthesized (as in this paper). Synthesizing cyclic peptides involves multiple steps just to get everything to fold correctly. So, it seems unlikely that the random cleavage of brain proteins that occurs in Cerebrolysin synthesis would yield any cyclic peptides.
Yes, I agree, I think it is pretty unlikely. But not completely impossible. As I said it should be pretty easy to find them if they are in the lysate via, HP liquid chromatography. Brain penetrant cyclic peptides should on the whole be significantly less polar than acyclic polypeptides of similar mass.
I’ve never heard of cyclic peptides. But I suppose it is possible.
Actually the HPLC study we cite talks about a similar possibility—they say the observed effects may be due to “cryptic peptides”, perhaps created by the lysing of larger proteins and peptides. It just seems very unlikely to me. To me, based on my metascience research, it’s a it easier to believe that the published literature is just plain wrong. Check out the HPLC paper—it’s he only we found doing that sort of analysis but it’s very detailed (https://analyticalsciencejournals.onlinelibrary.wiley.com/doi/abs/10.1002/dta.1817).