The medicinal chemistry of botulinum, ricin and anthrax toxins.
The potential use of weapons of mass destruction (nuclear, biological or chemical) by terrorist organizations represents a major threat to world peace and safety. Only a limited number of vaccines are available to protect the general population from the medical consequences of these weapons. In addition there are major health concerns associated with a pre-exposure mass vaccination of the general population. To reduce or eliminate the impact of these terrible threats, new drugs must be developed to safely treat individuals exposed to these agents. A review of all therapeutic agents under development for the treatment of the illnesses and injuries that result from exposure to nuclear, biological or chemical warfare agents is beyond the scope of any single article. The intent here is to provide a focused review for medicinal and organic chemists of three widely discussed and easily deployed biological warfare agents, botulinum neurotoxin and ricin toxins and the bacteria Bacillus anthracis. Anthrax will be addressed because of its similarity in both structure and mechanism of catalytic activity with botulinum toxin. The common feature of these three agents is that they exhibit their biological activity via toxin enzymatic hydrolysis of a specific bond in their respective substrate molecules. A brief introduction to the history of each of the biological warfare agents is presented followed by a discussion on the mechanisms of action of each at the molecular level, and a review of current potential inhibitors under investigation.
Hicks
Rickey P
RP
Department of Medicinal Chemistry, Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Washington, DC 20307-5100, USA. Rickey.Hicks@NA.AMEDD.ARMY.MIL
Hartell
Mark G
MG
Nichols
Daniel A
DA
Bhattacharjee
Apurba K
AK
van Hamont
John E
JE
Skillman
Donald R
DR
D000818:Animals; D000942:Antigens, Bacterial / Q000737:chemistry / Q000633:toxicity; D001427:Bacterial Toxins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000633:toxicity; D001694:Biological Warfare; D001905:Botulinum Toxins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000633:toxicity; D002384:Catalysis; D015195:Drug Design; D006801:Humans; D015394:Molecular Structure; D010455:Peptides / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D012276:Ricin / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000633:toxicity; D013329:Structure-Activity Relationship
D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D010455:Peptides; C030325:anthrax toxin; D012276:Ricin; D001905:Botulinum Toxins