Saturday, 23rd April 2011, we have just learned about peptide-based drugs from Bimo Ario Tejo through his public lecture “Peptide Based-Drug”. This event was initiated by Prof.Usman Sumo F.T. as metabolism class project (batch 2008). Thus, we are very thankful to him.
Our public lecturer, Bimo Ario Tejo, ph.D is currently a lecturer in Universiti Putra Malaysia (UPM) and live in Selangor, Malaysia with his wife and two-year old son. His research interest is currently circulating around protein and peptide chemistry. He got his Bsc in Chemistry from University of Indonesia in 1999, then he got his phD from UPM in 2004. Afterwards, he got his Postdoctoral from University of Kansas, USA in 2008. He was honored with Excellent Service Award 2009 from UPM in 2010 and many other including visiting reaseacher in University of Edinburg, UK and University of Stuttgart, Germany. He also made many publications and articles in journals. We proud to have him as our alumnus!
Here, I will try to summarize the lecture. I’ll make it as short as possible (but I guess it wouldn’t be). In the beginning, he convinced us that life is disasterous without drugs. No drugs means you could be died in a young age just like Queen Hatshepshuf of Egypt who died because of tooth infection (sounds ridiculous, isn’t it?). Besides, we don’t want to see the world suffered from a pandemic flu which can kill 50-100 million people, do we? So we need drugs to enjoy a longer, healthier, and happier life! Well then, no doubt that drug market is huge!
Next, he led to us to know how the drug works.
CONCEPT : Drug has to be adsorbed in intestine and must pass cell membrane to reach the target (disease). Cell membrane is a great barrier that not all molecules can pass it right away. Then, imagine how difficult the drugs is to pass the cell membrane and bind to receptor of the disease (which is the omset of disease to affect your body). We should keep that in mind that drug is inhibitor to receptor of the disease, so there must be a drug-receptor interaction : p interaction, H-bonds, hydrophobic contacts, and so on. Thus, a good drug must be hydrophilic as well as hydrophobic, has electronic charges, has steric atoms (but not too much, respectively). Confused? Me, too. Let’s refer to Lipinski Rule “Drugs are well absorbed if they have: Molecular weight < 500, log P (hydrophobicity) < 5, Hidrogen-bond donors < 5, Hidrogen Bond < 10. Remember, this is a “rule” that anyone could break it anytime. From the statement “MW has to be less than 500 (small molecules)”, actually there are many evidences that it causes problems, especially high toxicity.
So, to overcome the failure of small molecule drugs, please give a warm welcome to our new hero: PEPTIDE-BASED DRUGS!!!
Peptides are large molecules, indeed. But they fulfill the requirement of drugs: interaction between drug and receptor, remember? To synthesize the peptide, it is easier to make it in solid phase and all you need are peptide synthesizer, HPLC to purify the peptide, & MS Spectroscopy to analize the molecular weight. Abrakadabra, in less than 2 weeks, you’ll already have peptide!
But wait! There are two main problems regarding peptide molecules (because they are very easy to be chopped off into amino acids) :
1. Gastric acid in your stomach
If you take the drug orally, of course the peptide will be degraded to amino acids right away. To avoid the gastric acid, we have alternatives to deliver the peptide to our body:
a. Parenteral Peptide Delivery
In other words, we have to inject the peptide through our skin. It has 100% bioavailability (100% effective!) and fast. Yet it has some problems, such as it has to be administered by a well-trained person like doctor or nurse and many people also have a fear of needles.
b. Nasal peptide Delivery
We can insert peptide drug by inhale it. No doubt that our nose is a good absorber & it is an alternative to bring the peptide to our brain. But be carefull, nose is very sensitive so it is easy to get irritated. Moreover, the bioavailability (effectiveness) is also limited prior to its permeability.
c. Pulmonary Peptide Delivery
We may say that we can suck it into our lungs – just like a patient of asthma suck in his medicine – I supposed. Lungs have large surface to absorb the molecules & more rapid action compared to oral delivery. In contrary, our lung is also sensitive & we need small particle size to be absorbed by lung. I remember that one of the peptide drug using this method, Exubera (producted by Pfizer), has a problem with its package design – it is very big so you could use it as dough roller to make cookies/pizza – so it doesn’t fulfill consumers’ satisfaction and it was dumped a year after being released.
d. Buccal/Sublingual Peptide Delivery
Let’s say we can deliver the drug by dropping it through a part under the tongue. Remember the sweet immunization liquid we took when we were child? Yes, it is more likely like that. It is effective, but it shouldn’t be administered if you have an open sores/areas of irritation in your gums/mucous membrane.
Fiiuuhhh, there is still 1 problem ahead, guys. Recall that drug distribution is through the blood which has many proteases – enzymes that can chop off peptide bonds in peptide/protein – so let’s say that the problem is :
2. Proteases in blood
To trick the proteases so they do not cut the peptide bonds, we can do some chemical modification of peptide.There are some methods:
- By encapsulating/cover the peptide with lyposome nanoparticle.
- By stabilizing the peptide bond through conversion into peptide bond “mimic”.
- By using a cyclic peptide as prodrug (prodrug is an inactive drug that can be activated as our body metabolise it).
This long journey takes us to the dream of peptide-based drug: we hope for orally delivered peptide-based drug! It is surely the most comfortable way to consume the drug, isn’t it? So the consumers like it & we finally earn much money!! Hip hip hoorrraaayy!!