Published paper #1

Article:  Dolgin, Elie. 2013. “Antibody drugs set to revive flagging migraine target”. Accessed April 4th, 2013. http://www.nature.com/nrd/journal/v12/n4/full/nrd3991.html

 

I chose this article to analyze as my published paper #1 since this topic is all too familiar to me, as I myself have suffered with headaches and migraines since the age of 14; 7 years to date. I have researched intensely into this topic hoping for a solution to my own migraines.

This article first begins with the story of Emily S. who began experiencing headaches at age 7. Emily is now 31 years old and her headaches have now turned into severe migraines. Over these 24 years, she has tried a variety of prophylactic cures, none of which proved successful in alleviating her migraines. A prophylactic is a medication or a treatment designed and used to prevent a disease from occurring. These treatments used the anticonvulsant drug, Topiramate. However this drug caused short term memory loss and nausea. This combination of a tricyclic antidepressant and a beta blocker has deemed futile to these attacks.

The initial mechanism.

Statistics show that more than 10% of adults in the world experience unbearable migraine headaches. Even though 40% of “migraineurs” are good contenders for therapeutic prophylactic methods, only 1 in 3 of these people receives it. Four monoclonal antibodies (mAbs), currently in Phase I & II, are used to treat these patients, in hope that a problem plagued drug target is what is needed for permanent relief of this problem. These mAbs ultimately hinder the signaling of calcitonin gene-released peptide (CGRP). CGRP is a 37-amino-acid neuropeptide expelled by primary sensory neurons in the trigeminal ganglion during migraine episodes.

Developments.

Small molecule CGRP receptor antagonists have been in development for over a decade. A telcagepant, formulated by Merck & Co. was an investigational drug for the acute treatment and prevention of migraine. This drug gained recognition when it proved to exhibit results superior to placebo when it was used as an abortive therapy in Phase III trials. A placebo effect occurs when a treatment with no known effectiveness, such as a dummy pill, is given to a patient and the patient nevertheless has subsequent improvement in symptoms.  However, the company terminated the development of the drug due to escalated liver enzyme transaminase levels in patients that used the drug over an extended period. Nevertheless the trend of using injectable, prophylactic mAbs directed at CGRP or the CGRP receptor is flourishing.

Advancements.

By 2011, companies such as Amgen and Arteaus Therapeudics began testing new routes for the drug to target; the mAb directed at the CGRP peptide itself. Most recently, in January of 2013, Labrys licensed their drug to the renowned Pfizer Company. They postulated the dosage of once a month. “An antibody with a long half-life” said Alder’s pharmacists, a competing firm. Since the antibodies were not chemically similar to CGRP but instead blocked it, there would be no trace of liver problems.

Concerns.

Fears stemmed from the concern that the CGRP-directed mAbs would not cross the blood-brain barrier (BBB). This simply meant that the drug might not have a significant effect on the neurons in the brain. This apprehension was quickly dismissed on the view that both the peripheral and central systems could be stimulated instead of either or. Another issue was the presence of side effects. Due to CGRP’s ability to heal wounds easily, neuroscientists pondered upon the consequences of depleting the peptide and its long term effects. In the end it was decided that the drug would only prosper after the clinical benefits and injuries were evaluated, with the advantages outweighing the disadvantages. Despite the drug’s high cost of production, it earned more 10,000 times more than its initial cost in profits. In conclusion, the drug proved worthwhile for companies such as Artaeus amidst of generic market of mAbs.

Additional references:

• http://en.wikipedia.org/wiki/Telcagepant
• http://en.wikipedia.org/wiki/Placebo
• ‘Placebo Effect’ May Be Common in Headache Treatment http://www.webmd.com/migraines-headaches/news/20110523/placebo-effect-may-be-common-in_headache-treatment?page=2&rdspk=active

Quiz on Amino Acids and Proteins

1) Glutamic acid is one of the two acidic amino acids. What is the other?

a) Methionine

b) Aspartate

c) Arginine

d) Histidine

e) Threonine

2) Which amino acid differs from Alanine in that one of the methylenic hydrogens is replaced by a hydroxyl group?

a) Cysteine

b) Threonine

c) Serine

d) Methionine

e) Isoleucine

3) Isoleucine is one of the two amino acids that have two chiral centers. What is the other?

a) Aspartate

b) Fructose

c) Threonine

d) Glycine

e) Alanine

4) Leucine and Valine are two of the three amino acids having branched hydrocarbon side chains. What is the third?

a) Lysine

b) Isoleucine

c) Serine

d) Glycine

e) Threonine

5) What amino acid has a secondary amino group, rather than a primary α-amino group?

a) Phenylalanine

b) Serine

c) Glycine

d) Proline

e) Alanine

Amino Acids and Proteins Wordle

Explanation of Amino Acid Groups.

Amino acids differ when they have different R Groups attached to them. Learning the structures is important, but understanding why  these molecules are arranged and placed where they are is equally important when learning and explaining this topic.

These groupings can be divided into :

1) Non-polar, aliphatic R groups. 

Aliphatic R groups are nonpolar and hydrophobic. Hydrophobicity improves with increasing number of C atoms in the hydrocarbon chain. While these amino acids prefer to remain within protein molecules, alanine and glycine are ambivalent. This means that they can be inside or outside the protein molecule. Glycine has such a small side chain that it does not have much effect on the hydrophobic interactions.

2)Polar uncharged R groups.

There are eight amino acids with polar, uncharged side chains. Serine and threonine contain hydroxyl groups. Asparagine and glutamine contain amide groups. Histidine and tryptophan contain heterocyclic aromatic amine side chains. Cysteine has a sulfhydryl group. Tyrosine has a phenolic side chain. The sulfhydryl group of cysteine, phenolic hydroxyl group of tyrosine, and imidazole group of histidine all show some degree of pH-dependent ionization.

3) Aromatic R groups.

This group is identified by having an unsaturated ring containing double bonds in a conjugated form, especially containing a benzene ring. Examples of Aromatic R groups are :  Phenylalanine, Tyrosine and Tryptophan.

4)Positively charged R groups.

In a neutral solution, the R group of a basic amino acid may gain a proton and become positively charged.  Interaction between positive and negative R groups may form a salt bridge, which is an important stabilizing force in proteins.

5) Negatively charged R groups.

In a neutral solution, the R group of an acidic amino acid may lose a proton and become negatively charged.including aspartic acid (aspartate) and glutamatic acid (glutamate).  In a neutral solution, the R group of an acidic amino acid may lose a proton and become negatively charged.

6)Sulfydryl groups.

These R groups contain a sulfur atom (S).  The disulfide bond formed between two cysteine residues provides a strong force for stabilizing the globular structure.  

For the structures and additional information on Amino acid groups, refer to the Amino acid and proteins part 1 lecture linked below.

Why do we need the 20 essential amino acids?

We have been taught about the 20 essential amino acids, but do we know why they are essential to our bodies? Below is a list of their responsibilities and functions. Alanine: It is one of the most significant among the 20 common amino acids. It offers energy to your system. It releases into the blood stream during exercise time and induces carbohydrate-consuming effect to the health system. It promotes enhancement in the area of protein synthesis and nitrogen balance.Arginine: Synthesized normally in the body, arginine is known to be a semi-essential amino acid. Sometimes more is required than normal production. Deficiencies may include poor wound healing, weakness in muscles, hair loss, irritations in skin, and constipation.  Asparagine: It is needed to maintain homeostatic balance in the nervous system. Amino acid transformation and ammonia synthesis are largely dependent on asparagine. Aspartic Acid: Aspartic acid is one of two acidic amino acids belonging to the group of 20 common amino acids. It promotes enzyme activity, maintenance of solubility in the body, as well as homeostasis in ionic characters of proteins. Cysteine: It is present only at the rate of 2.8% into proteins but it provides the 3-dimensional stability of the protein molecule. It also plays a crucial role in the metabolic process of many important enzymes.  Glutamic Acid: It is responsible for transportation of glutamate and other amino acids to the blood barrier.  Glutamine: Glutamine is able to eliminate excess ammonia from the body system. It enhances immune system. Apart from that, glutamine possesses anti-anxiety property that permits the mind to be relaxed. Glycine: It helps in the transformation of harmful toxic substances within the body to a non-toxic form.  Histidine: Histidine is required for infant development. Histidine deficiency may result in eczema, a kind of skin disease. There are few genetic disorders that promote non-metabolic state for histidine. This results in speech disorders and mental retardations among infants and toddlers.  Isoleucine: This amino acid is particularly important for stimulating the brain in order to produce mental alertness. Leucine: It is particularly effective for producing other essential biochemical compounds in the body. These chemicals are important for producing bodily energy and mental alertness.  Lysine: Lysine is important for proper growth, and it plays an essential role in the production of carnitine, a nutrient responsible for converting fatty acids into energy and helping to lower cholesterol. Lysine appears to help the body absorb calcium, and it plays an important role in the formation of collagen. It functions against the  herpes virus in particular by providing body required nutritional supplements.  Methionine: It functions at initiating the translation of messenger RNA.Phenylalaine: This amino acid profoundly affects brain cells at biochemical level. Proline: It significantly affects human nutrition. It is believed to act as a source of nitrogen.  Serine: Serine is intimately related to various bodily functions such as fat metabolism, tissue growth, enhancement of immune system and many more. It is an essential ingredient of brain protein.  Threonine: It helps in the maintenance of protein balance and also in assisting collagen formation.  Tryptophan:  This is particularly needed in the body for the production of vitamin B3.  Tyrosine: This is crucial in building link between dopamine and norepinephrine. It also reduces fat by suppressing appetite.  Valine: It is effective in promoting tissue growth and maintaining nitrogen balance in the health system.

Identifying the polarity of amino acid bonds.

A bond is said to be polar when there is a large amount of electronegativity difference between the atoms in a bond. Partial negative charges are found on the most electronegative atoms and the others are deemed partially positive.

Here are a few tips to aid in identifying the polarity and charges of amino acids.

1) If the amino acid side chain is a hydrocarbon, the amino acid is non-polar. There are 2 exceptions to this: Proline and Tryptophan. These exceptions however can easily be seen due to their steric hindrance.

2) If the amino acid chain has an atom that possesses electronegativity or polarity, but no charge, then the amino acid is polar uncharged.

3) If the amino acid has a charge on the side chain, it is polar.

Below is a table of standard amino acid abbreviations and their side chain properties.