‘Encrypted’ peptides could be wellspring of natural antibiotics | Hacker News Reader

‘Encrypted’ peptides could be wellspring of natural antibiotics

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Another interesting Peptide.

There is evidence of BPC 157 can help heal IBS, etc.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5333585/

It has other healing properties related to ligament injuries.

https://pubmed.ncbi.nlm.nih.gov/21030672/

Another study on its benefits regarding blood vessels.

https://pubmed.ncbi.nlm.nih.gov/23782145/

An article from Ben Greenfield

https://bengreenfieldfitness.com/article/supplements-article...

A source for anyone interested.

https://infiniwell.com/products/bpc-157

Did you find also studies on long term effects? I couldn’t find any

I am under the impression there are few/none. It is a something your body makes but as you age, less and less is produced. There have been a lot of folks in athletic circles who use it regularly to heal injury. It one of those things that Big Pharma can't patent so there is no interest in producing it.

I checked with a close friend who's spent the last 30 years in research on new antibiotics. Regarding peptides, he says, it's well-known that they're effective, but they make poor "drugs if you define 'drug' as something that you can inject or put in your mouth, have it circulate through the body, arrive intact at the site of infection, and have an effect. They usually fall apart en route; they also often induce an allergic response when you inject them."

I'm no expert nor have I used any but I've read that some people snort them nasally like saline, on the r/peptides subreddit.

This might be my brain making things up but I think I've also heard of people taking them ocularly, putting a few drops in their eyes. I don't know where I would have read that though.

Can anyone shed light on how complicated, slow, and costly it is to synthesis these proteins in vitro?

This article might help: https://cen.acs.org/articles/89/i22/Making-Peptides-Large-Sc...

By hand a skilled practitioner of t-boc chemistry can couple one amino acid per hour, though t-boc (boc) is disfavored since workup involves using 100% HF. Fmoc is the more popular technique and it's more like two hours.

Robots can do this too, there's no real time benefit (but a robot can do more than 10 peptide couplings a day and doesn't need a lunch break -- though I guess neither does a grad student).

Chief problems include: you need super concentrated protected peptides, which are highly insoluble in just about any solvent, so your system needs to have tons of filters, plus stuff gunks up your apparatus over time anyways. Then, fmoc craps out at about 20 amino acids if you're lucky, due to exponential decay of yields (99%^20, not to mention later yields can be lower due to peptide chains curling on themselves), boc can go longer. Not to mention separating what you want away from side products gets difficult.

Finally the wastefulness: boc chemistry you're throwing away atoms almost 1:1 with what you're putting in to the peptide. Fmoc is typically 3:1. The solvents you use are these nasty greasy fishy smelling solvents (dmf, nmp). And the activating agents are really expensive compounds that you will slowly become allergic to if you keep working with peptides.

I personally have, though unpublished work, the first total (artificial) synthesis of ubiquitin, that I did as a grad student in my first year. Although it's 76 amino acids we synthesized it in two parts and stitched them together using a technique called "native chemical ligation", though we did something special called "folding-assisted native chemical ligation".

I would have imagined labs these days just synthesise the mRNA and then let a ribosome do it’s work?

You can't always do that. Suppose you want a peptide with an unnatural amino acid... Or a natural amino acid with a specific post translational modification...

Unnatural amino acids can be done though - there's been a bunch of work on getting/finding ribosomes which will polymerize all sorts of whacky stuff.

I'm aware, I used to work next to Floyd Romesberg. Yields are low, suppose you want to put TWO strange things in. Suppose you want to build a depsipeptide (or a dipeptide analog with C=C linkage). Suppose you need a 12-mer (ribosomes are very bad at short peptides).

Not saying it's easy but ribosomal synthesis of consecutive non-canonical amino acids has been achieved by some groups (https://www.cell.com/cell-chemical-biology/fulltext/S2451-94..., https://pubs.acs.org/doi/10.1021/jacs.8b07247), and many of these peptides are extremely short. Figure 5 of this manuscript describes successful applications of this for hit identification often in the context of massive peptide library screens, https://pubs.acs.org/doi/10.1021/acs.accounts.1c00391

it's not really a generalizable solution, though, because suppose you need an unnatural AA that needs a specialized ribosomal cavity and that cavity hasn't been developed yet. And you need the material by a year's time. You are not going to evolve a ribosome to make your peptide. And, there are post-translational modifications that are too big to fit into ANY cavity, though in theory you could use tricksy chemistry to figure out a downstream processing step, that chemistry may not exist yet, or it may require a pure enzyme that is a pain in the ass to obtain, etc. etc. Finally, charging the correct tRNA is not necessarily easy or efficient.

Unlike well-designed programming architectures, biology is usually not "trivially composable". Oddly, SPPS is. Yes, there are corner cases, but those are more the exception than the rule.

even better is to put it in yeast or e coli and let them be your factory

There is innovation in this space. From green chemistry initiatives to replace hazardous solvents by CROs/industry invested in large-scale production of peptides, https://www.bachem.com/news/bachem-novo-nordisk-redesign-spp..., to routine solid-phase synthesis of peptides greater than 100 amino acids in hours (https://www.science.org/doi/10.1126/science.abb2491, being commercialized here https://www.amidetech.com/)

Lol at the first one, replacing nmp with DMSO/EtOAc while an improvement in toxicity, it's still expensive, toxic, and hard to remove/recycle.

I had to Google ubiquitin to verify that this wasn't a dryly elaborate reddit-surprise thread. It is indeed a well-named compound, ubiquitous among eukaryotes, and even if "boc" and "fmoc" are basically just fizz and buzz to me, it sure sounds like you know what you're doing.

Our startup routinely orders the synthesis of hundreds of peptides for technology validation and drug discovery research (not suitable for human consumption). Costs for a small quantity through a contract research organizion can be $200-$2000 USD per peptide depending on desired purity, length, and chemical complexity. For some applications peptide arrays are suitable, and can drive the costs down to $10 USD per peptide or lower. In both cases, the turnaround time is 4-6 weeks, even though a peptide chemist could do the job in about half the time for a rush order.

How do you verify they got the structure right? If it's like everything else you order online these days...

you can put it on a mass spectrometer

It is a little known fact that peptides are becoming really big in the athletes/recovery/PED space. There is a lot they can do and there are so many. However we are also learning that they can cause a lot of unintended disease, cancer, etc as well.

Yikes, I know there are a lot of "healing" peptides sold online for various conditions. Very spare documentation though

It’s scary, but I’m taking some of these myself. I had food poisoning and was diagnosed with IBS-C a few years ago and my life has been pretty deranged since then. Couldn’t sleep more than a few hours a night, couldn’t think, went from a BMI of 22 to 18. No help from doctors, or years of different drug therapies; I’ve tried everything that medicine has to offer. Also could not get my blood pressure down to save my life even on multiple meds. Fecal matter transplants helped quite a bit but still couldn’t get BP down, get good sleep, etc. Only when I started using some peptide suggested on Reddit was I able to normalize my BP and see improvements in other areas. It’s scary and I don’t recommend it (my doc certainly doesn’t, but he doesn’t endorse any of the therapies that have improved my wellbeing); I don’t want to be a guinea pig for a peptide that has a limited amount of human data to back it up; but the alternative of not using it is just so unlivable and having it solve my BP problem alone is a gift in itself. I hope I’m not shooting my future self in the foot by using these but I don’t see any alternative option currently. It sucks to be sick when medicine still hasn’t figured things out.

I've got similar health problems, and I'd love to know more about what worked for you so I can research it.

Thanks; I'm sorry to hear about your health problems I know how debilitating they can be. Hope your case is not as bad as mine. I'm currently self administering FMTs which I get from someone in my local community. I have tested the stool of dozens of people (which is so expensive) and have settled on this donor who has a decent stool profile.

An alternative to that may be trying to get stool from humanmicrobes.org or a more "legit" way which is through the center for digestive diseases in Australia. I don't know if FMT's are helpful for all IBS patients (the research is not there yet) but anecdotally it seems like the most desperate IBS patients end up trying it to varying efficacy. I can't recommend FMT as I'm sure everyone's pathology is different and there are more traditional therapies that may work such as low FODMAP, rifaximin, or meds that increase/decrease intestinal transit time. For me, all of those therapies are embarrassingly ineffective and I think that IBS patients should at least know that FMT therapy is a thing; since it has lead to remission for many community members which gives hope that there may finally be a treatment for the most desperate.

So the FMT helps in my case as well as the BPC-157 which someone else linked in the comments. I was quite surprised when my resting heart rate and blood pressure returned to my pre-disease levels within a day or two of starting the peptides. I have probably tried 3 or 4 dozen drugs at this point (mostly doctor recommended but also some from my own research); none to any effect, so seeing quick results from this new compound was shocking. I now also have more of type 2-3 stools rather than the unescapable type 1 that has plagued me ever since the diseases' inception. So that's good. I've only been using the peptides for a month so don't know what to expect. I am hoping if I can mega dose with some FMT and keep using the peptides maybe I could get into remission. Who knows. Luckily I am able to function as an engineer again for the first time in years (the brain fog is less remarkable now) so I am hoping things will return to normal but only time will tell. I hope this information is helpful but feel free to reach out if you have questions or just would like to chat because I know how lonely and lost in translation these type of health maladies can be.

Does BPC-157 have to be injected? (I thought peptides were fragile and need to be refrigerated typically)

I don't know the answer to that; I inject mine, I have read that other people squirt them into their mouth, which I have not tried yet. The results are just so good from injecting it that I can't imagine ingesting it orally being better; but I should give it a shot.

You can take it orally for gut problems.

How long did it take you to see results after taking them?

Pretty much right away for both. I think it's because with my condition; eating seems to be incredibly inflammatory. So, whenever I eat anything, I my blood pressure spikes tremendously, heart rate jumps ~15 points, I get brain fog & all kinds of other symptoms, which last several hours only to subside when I start to get really hungry again. Of course.. at that point I'm hungry, and it becomes increasingly hard to not eat.. so once I cave and eat the cycle starts over again. I currently eat twice a day and have tried cutting that down to once a day but at that point my meals are so large that the falllout is just terrible. The goal is always to eat as little as possible while maintaining adequate nutrition, which is hard, because I also don't seem to assimilate nutrients from food very well either.

Anyways, if I am taking a lot of fecal matter and using the peptides; the fallout I get from eating is not as bad. There are still other issues, but it seems to work at at least within a few days with the fecal matter and instantly with the peptides. Very sadly, I've noticed the benefits go away pretty quickly once I stop using each treatment as well. It really is a nightmare, but I am sure others have it worse.

I'm curious: do you have noticed any connection between what you eat (macro and micro) and the symptoms level? Because what you're describing could match dysbiosis and/or leaky gut, and you seem to have already dug really well into your condition.

I've tried limiting certain macros and found that it doesn't really make a difference. I did try do to all meat at one point and got a lot worse. The devil is in the details in regards to the micronutrients. I am absolutely unable to tolerate most foods and can only really eat a handful. I can eat most fruits and can eat meat products but cannot eat most vegetables. Which sucks, because you can only eat so much fruit a day and I think a good diet should be vegetable based. Eating most vegetables though, causes me to lose weight, have panic attacks, vertigo, ezcema, peripheral edema, etc; all manners of strange symptoms. It probably is "leaky gut" related but I don't know.

Holy crap you pretty much just described me exactly. My stomach problems are minor but everything else you described is me to a tee. Interestingly the doctor has sent me to get tested for various stomach inflammatory diseases for completely different reasons, but they all came up negative.

Just googling now it seems there is no real test for IBS. How did you know that was the cause? Also, I've taken peptides before for different reasons, which ones helped you with your stomach?

That's crazy. Docs diagnosed me with IBS based on some tests that I had done at the time (anti-vinculin antibody, SIBO breath test, etc). I don't really know. I do know that I don't poop often enough and that the longer I go without pooping the worse all my symptoms get. Interestingly, like you, I was tested for many inflammatory diseases of the gut too, and they all came up negative; so the tests kind of give me a mixed bag of signals. I also have crazy food sensitivities so it certainly must have some relation to the gut. I'm just doing the BPC-157 right now; some people have recommended others but I haven't tried anything else yet.

This might sound a bit crazy given what you said, but have you tried light exercise straight after your daytime meal? I too get completely incapacitated by food, my heart rate goes up, and i usually just lie down (haven't measured my blood pressure), but if I go to the gym and do light aerobic exercise for 45 minutes (keeping my heart rate around 135-145) then the worst of the symptoms are abated. Also, the brain fog doesn't matter if you're on a treadmill, it's actually quite a good thing to zone out. Most importantly it allows you to be productive during that time, and later on when you are back to normal you have more time to do other things as you have already gotten your exercise out of the way.

That's an interesting idea! I have a walking treadmill that I use at my desk which I usually do a few miles a day on; but I'm definitely no where near 135-145BPM. I think I will give that a shot tomorrow after my next meal; thank you so much for the suggestion!

>The goal is always to eat as little as possible while maintaining adequate nutrition

That sounds like you're (involuntarily) on a CRON diet; calorie Restriction optimal nutrition.

https://en.wikipedia.org/wiki/CRON-diet

Pretty much. It's really hard to maintain long term because I end up eventually getting so hungry that my brain starts becoming obsessive about food. So my attempts are only half successful.

> we are also learning that they can cause a lot of unintended disease, cancer, etc

From what I've read, as a layman, many peptides can increase cell growth which is sometimes associated with tumor growth, but they may also have a stabilizing effect on cell growth which wouldn't cause cancer at all, and could even be beneficial. I don't think there has been any evidenevidence linking peptides with cancer though. Would be eager to know if anyone has seen such evidence.

Peptides are actually "short bits of protein" - proteins is what makes cell work. So no wonder here, that they are really big and can do a lot.

There is one thing that worries me about this. See humans and pathogens have a common interest. We don't want to be killed. And they don't want to kill us. So how can this be achieved? By using stronger defences in key parts of the body. Pathogens have no incentive to circumvent them, by respecting the boundaries they can infect and spread without killing with all of the issues that come with that. But if we take the best defences and apply them everywhere this balance could be permanently disrupted. Now whether this all applies to these peptides is an open question, but I hope they will consider risk/reward carefully.

We've eradicated diseases before and nothing happened (e.g. smallpox, polio). Also, the only risk is that the bacteria gain resistance to these peptides. Which isn't even that great of a risk - if humans express these peptides, we've been trying these antibiotics for millions of years. Clearly nothing bad happened.

I think you are missing my point. If there is an antibiotic peptide that's only expressed in the brain, then there is no benefit for bacteria to evolve resistance to it. It would make us too sick. Afflicted people would stay home which would reduce spread. Normally diseases evolve the opposite way: to be less and less harmful. This is known as Smith's "law of declining virulence". So they may even evolve vulnerability.

If you take that some peptide and and put it inside your whole body, then evolving resistance becomes a high priority. Bacteria who don't do it stop spreading.

And once they have evolved resistance there is no going back. You can't send a security update with new brain specific anti-biotics.

Uh, is there any logical reason to think that the genome of a human - or any other higher level organism - has coded for unique antibiotic combinations that, e.g. various fungi which have spent the last billion years in daily fist fights with bacteria? I'm all for trawling the DNA of any creature for magical recipes, but our DNA has to code for a lot, and immune response is only a small part of it. Seems like it would be a lot more efficient to focus on phages or fungi and study what peptides they activate in response to specific bacteria, than just throwing endless processing cycles at the human genome hoping for, uh, grant money?

I wish some money would be thrown at researching Kambo (an amazonian tree frog with a poisonous secretion used by a few indigenous tribes touted for its peptide cocktail, "the vaccine of the forest"), considering its growing use. Seems like a better place to start than some of these stabs in the dark.

If we were just interested in bioprospecting for new antibiotics, sure, there's more phage genome out there than human. But there's a unique value in understanding how human antibiotic peptides work (or fail to work). Does expression of human antibiotic peptides decrease with age? Are they only expressed in certain tissues? There are important implications that we'll never uncover through non-human sequence mining. Additionally, human-derived peptides will probably have fewer side effects if used therapeutically, you never know what kind of immune response some random phage peptide will elicit.

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