Human genome mapping and ACE inhibitor drug discovery

¶ … Genome Project on Drug Design and Discovery

The advances that have been made due to the mapping of the human genome are substantial and along with this are substantial advances in medicine and most specifically in pharmacology. It was reported recently that "a further human homolog of ACE, referred to as ACE 2, was identified and shown to be an essential regulator of cardiac function. It differs from ACE in that it contains a sing zinc-binding catalytic domain, is a carboxypeptidase with preference for carboxy-terminal hydrophic or basic residues, and is not affected by ACE inhibitors." (Riordan, 2003) These ACE inhibitors are now the chosen treatment for treatment of hypertension and congestive heart failure, left ventricular systolic dysfunction and myocardial infarction.

SEARCHING THE PUBLIC GENOME DATABASE

Time Asia reports that "sifting through the human genome for therapeutically useful gems...requires a well-designed search strategy combined with powerful technology. At Millennium, housed in a factory that once stamped out heart shaped candy boxes for Valentines' Day, that strategy is embodied in Zeus, whose job is to find the handful of genes among the genome's tens of thousands that are key to individual diseases and thus key to making effective medications." (Lemonick, 2001)

III. IDENTIFYING AND ISOLATING THE DRUGS

Stated in the Time Asia publication is that: "Testing the enzyme on tissue cells from different organs in the body, the scientists showed that whereas the original ace acts broadly on many tissues in the body, ace-2 is particularly active in heart and kidney cells, where it might be more effective in controlling high blood pressure." (Lemonick, 2001) Since the team was already knowledgeable of how ace worked on the molecular level they knew which test to use to determine whether the same effects came from ace-2 and it was found that it did.

IV. TESTING ON ANIMALS

The research team and scientists worked their way through Millennium's library that contained: "700 different classes of compounds for molecules whose chemistry made them candidates to clamp down on ace-2 activity. Then, with the help of protein-modeling software they manipulated the chemical structure of their new inhibitor to give it optimal binding affinity with the ace-2 receptor. In about two years, Millennium had created a new blood-pressure-drug candidate that is now being tested in animals." (Lemonick, 2001) This team and their technology had accomplished in a mere two years what it previously would have taken a decade to accomplish.

IV. TESTING ON HUMANS

The only thing that is lacking at this point according to all reports is for testing on humans to be completed. The Time Asia articles states: "The last step for the ace-2 inhibitor, as for any drug, is human clinical trials. Because the U.S. Food and Drug Administration requires such rigorous testing, this is by far the most expensive part of drug development. So for human trials in some cases, Millennium has formed partnerships with large pharmaceutical companies that have the necessary resources and will share in any eventual profits." (2001)

SUMMARY & CONCLUSION

According to the work entitled: "Brave New Pharmacy" published in Time Asia (2001) "When the human genome was sequenced...scientists finally gained access to the full text of God's reference manual; the 3 billion biochemical 'letters' that spell out our tens of thousands of genes. These genes, strung out along the 46 chromosomes in virtually every human cell, carry the instruction for making all the tissues, organs, and hormones and enzymes in our body." (Lemonick, 2001) Lemonick states that: when scientists finish decoding these instructions.."..they should have a better understanding of precisely what happens, down to the molecules within individual cells, when the body malfunctions....if you understand the genetic basis of a disease, then you can predict what protein it produces and set about developing a drug to block it." (2001) In fact the traditional method used by physicians of the patient working their way through several drugs before finding one that works, such as in the case of high blood pressure will be transformed "in the new era of genomic medicine" because this "halting, inefficient approach should give way to something much more rational and systematic." (Ibid) Therefore it can be understood that the traditional "trial and error" methodology of medicine discovery of the past century and the many centuries preceding it has ended with the new methodology being that of "yielding drugs to design [as scientists are now] "armed with blueprints for our genes, can identify the individual molecules that make us susceptible to a particular disease. With that information -- and some high-speed silicon-age machinery -- they can build new molecules that home in on their targets like well-aimed arrows." (Elmer-Dewitt, 2001) These new developments in science and pharmacological development will do away with many side effects that patients have had to suffer in the past as the most effective medicine is sought by the physician for the patient and as well the more effective and systematic treatment of disease is now possible.