Ultrafast Drugs for Interdicting Enzyme Function Now in Clinical Trials

Drugs that operate to curtail enzyme function during transient transition states, when enzyme function spikes upward, are now in clinical trials.

To say that enzyme action is fleeting is a prodigy of understatement: Enzymes take just a femtosecond – a quadrillionth of a second – to modify their three-dimensional structure into their “most reactive form, trigger a chemical reaction”, then revert back to their original shape. Yet we are now able to biochemically effect action in this vanishingly transient regime, to interdict “the chemical reactions that sustain some of our deadliest pathogens [when they] cause disease.” Further, this capability “could lead to antibiotics that won’t trigger [pathogenic] resistance.”

The idea that enzyme potency spikes at barely detectable “transition states” was suggested by chemist and Nobel laureate, Linus Pauling, as early as 1946. Until recently, however, this was all academic. As “Vern Schramm at the Albert Einstein College of Medicine in Yeshiva University, New York” pointed out: What the enzyme’s transition state looked like was denied everyone.

No longer. With use of computational and molecular modeling techniques, Schramm has, through about a decade of labor, reconstructed the transition state of the enzyme. Using his results, Schramm has been able to formulate drugs that effectively render enzymes impotent.

One such drug “neutralises a key enzyme in the malaria parasite, Plasmodium falciparum. Owl monkeys infected” with the illness (which, if left untreated, usually proves fatal) were cured of the illness “after a week-long course of the drug.” Two of Schramm’s drugs – on for treating gout, the other for treating leukemia – are already in clinical trials.

Because Schramm’s drugs are so specific in their effect, there is the possibility of considerably lower dosages in their administration. Further, by curing disease through disruption of enzyme-mediated biochemical pathways in disease processes rather than attacking the pathogens themselves responsible for disease (and thereby putting the pathogens under evolutionary pressure to mutate and develop a resistance to drug action) Schramm’s drugs may become the first drugs to be immune to pathogenic resistance.

In this connection, “Schramm has developed a drug” disabling an enzyme involved in biochemical communication between Escherichia coli “and the cholera-causing pathogen Vibrio cholera.” Laboratory results show no diminution in drug efficacy against the pathogen up to the 26th generation of the pathogen. “The next step is to find a company to develop the drug further.”

(Reference: Woodbury, Margaret A. 2012. “Superfast drugs target shape-shifting enzymes.” New Scientist. 13 March)

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