Toxicity (or lack of it) of peptide compounds

[polymath]

Is there any reason to expect that a small molecule peptide drug would have carcinogenic or other unspecific toxic effects less likely than a non-peptide compound? It would seem logical that a peptide compound would not produce reactive metabolites (peroxides, etc.) any more likely than the amino acids it is made from. Of course, peptides may have the problem of poor BBB penetration or short half life compared to non-peptide drugs.

If a novel compound with peptide structure is less likely to be toxic than other kind of compounds, it may be logical to favor peptides when inventing new "research chemical" drugs. Unfortunately, only the opioid class of drugs seems to have a lot of peptide counterparts to ordinary ones. It's difficult to find a dopamine reuptake inhibitor or NMDA antagonist with a peptide structure.

 

[Hodor]

Heh, someone tell that to the "aspartame = satan!!1!" brigade (aspartame being the methyl ester of the dipeptide Aspartyl-phenylalanine).

The thing about peptides (besides the shitty bioavailability) is that they are that much harder to synthesize than regular synthetic compounds. For each amino acid you introduce, you have to factor in a deprotection and a coupling step, followed by a capping and possibly a washing step. Purification of the final product is also going to be trickier.

And while you could argue that the individual (unmodified) amino acids aren't going to form toxic metabolites, there is nothing saying that your final product cannot negatively affect you in other ways (the toxins in death cap mushrooms, amanitin and phalloidin, are both peptides, for example).

Plus, many peptides involve enzymatic or chemical modifications to their constituent amino acids, which may fundamentally change their properties. There's the famous example of the Point-Saint-Esprit incident, in which the treatment of flour with nitrogen trichloride (used as a bleaching agent) led to the methionine in it being converted into the neurotoxin methionine sulfoximine, causing excited delirium and seizures and leading to allegations of secret CIA experiments involving LSD being conducted in France (not denying that the CIA did a lot of shady human experiments, but this being the 1950's, it would have been far more convenient for them to conduct such an experiment on African-Americans in the Deep South)

 

[polymath]

Quite appropriate criticism, but the fact that evolution has managed to create a really toxic peptide to protect a fungus doesn't tell much about the probability of a random peptide having a completely unexpected toxic effect. Aren't there some kind of automated peptide synthesizers?

Some statistical analyses have been made about the toxicity of peptides: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0073957 .

 

[polymath]

Here's something about peptides that cause a stimulant effect by a mechanism that differs somewhat from more common dopamine releasers or reuptake inhibitors.

https://molecularbrain.biomedcentral.com/articles/10.1186/s13041-018-0409-0

Attention-deficit hyperactivity disorder (ADHD) is a neurocognitive disorder characterized by hyperactivity, inattention, working memory deficits and impulsivity. Its worldwide prevalence is estimated to be 3?5% in children and adolescents. The mainstay treatment for ADHD is stimulant medications (e.g. methylphenidate), which increase synaptic dopamine by directly blocking dopamine transporter (DAT). Although these pharmacological agents are effective, they are often associated with various side effects including risks for future substance use disorders in ADHD patients. Here, we investigated an interaction between DAT and dopamine D2 receptor (D2R) as a novel target to develop potential therapeutics for the treatment of ADHD by using an interfering peptide (TAT-DATNT) to dissociate this protein complex. We found that TAT-DATNT promotes locomotor behavior in Sprague-Dawley rats. Furthermore, using in vivo microdialysis and high-performance liquid chromatography, we found that the disruption of D2R-DAT elevates extracellular dopamine level. More importantly, the interfering peptide, TAT-DATNT, attenuates hyperactivity and improves spontaneous alternation behavior in spontaneously hypertensive rats (SHR) ------ a common animal model of ADHD. This work presents a different means (i.e. other than direct blockade by a DAT inhibitor) to regulate the activity of DAT and dopaminergic neurotransmission, and a potential target site for future development of ADHD treatments.