What are the important steps in designing peptide-based drugs? We have anti-cancer peptides that display anticancer activity against a wide range of cancer cell lines. We also checked they are not cytotoxic to normal cells. How should we proceed further?
If you are currently limited to in vitro assays I would recommend doing human and murine plasma stability, sometimes there is a problem with peptides and plasma peptidases. Plasma protein binding (PPB) could be also of use to evaluate free fraction of your pepide. Depending on peptide nature and your capablilies I would suggest to run BBCEC assay to see if it gets to the brain. Based on that you can leverage your studies of neurotoxicity.
If you can do in vivo - then you can do efficacy (xenografts, singenic, transgenic). Then PK in 3 doses, single and multiple doses, bioavailability, and single and multiple tolerated doses. Based on that you can assess therapetic index and design your tox program.
Before all these steps, I'd advise you to check the novelty of drug. If there is no problem, for each drug there is an ADME check. These are absorption, distribution, metabolism and excretion. But, before these, you should check the immune activity of that peptide, whether it induces some immune- or inflammatory-reactions. Then, bioavailability of drug should be checked, i.e. how much can it stay in blood naked. After that, if the time it staying doesn't feel enough, it would be entrapped inside a nano- or micro-particle (because it is a protein, there is a big chance that it won't be able to stay for a long time due to proteinases present in blood and tissue fluids). After these, the ADME check should be done (the newest technique is to check it in a bioprinted tissue, but you also can check it in an old way, on a live animal).
These are the short summary of what I recall for now. If I'd remember more, I'll note here.
I wish it ws helpful.
Cheers.
Thanks for suggestions. I believe ADME is checked for small molecules not for peptide.
An in Vivo assay is critical. Pharmacokinetics would be necessary. If your peptide has a certain effect on cells, for example something measurable in a short term assay, then you can test it in A bioassay. Or you can set up mass spec to do pharmacokinetics to see what it's half life is probably by injecting IV and possibly IP. If it has a long enough half life in Vivo, then you can choose a suitable cancer model to test it. You can also see if it can be orally delivered. But it is important to get a ""proof of concept" experiment as soon as possible before a lot of work is done to modify the peptide.
If you are currently limited to in vitro assays I would recommend doing human and murine plasma stability, sometimes there is a problem with peptides and plasma peptidases. Plasma protein binding (PPB) could be also of use to evaluate free fraction of your pepide. Depending on peptide nature and your capablilies I would suggest to run BBCEC assay to see if it gets to the brain. Based on that you can leverage your studies of neurotoxicity.
If you can do in vivo - then you can do efficacy (xenografts, singenic, transgenic). Then PK in 3 doses, single and multiple doses, bioavailability, and single and multiple tolerated doses. Based on that you can assess therapetic index and design your tox program.
I am working on a cationic peptide and it also is not harming the normal cells as it binds with the cancer cells due to high negativity on the outer layer due to phosphotidyl serine. A lot of research is already being going on Cationic peptides. some peptides also have undergone initial stages of clinical trials.
@Amir May I know reason why it binds to cancer cells not to normal cells. Specificity is one of the major issue. Most of anticancer peptides also kill other cells als.
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