ENZYMES 



enzyme. Clearly, little progress will be made along rational lines in 

 chemotherapy unless progress in the enzyme chemistry of infectious 

 organisms is stimulated. Many are not convinced that progress in 

 chemotherapy can come from that direction. "Suppose," they say, 

 "you find the enzymic Achilles' heel, how are you going to find the drug 

 to inhibit that enzyme?" As an example of the direction from which 

 the solution might come, the chemical nature of the prosthetic group 

 or active groups of the enzyme which turns out to be the weak point 

 might provide the necessary clue for the synthesis of specific inhibitors. 

 None will maintain that the solution will be easy, but experience has 

 taught us that the possibilities of solving a problem are greatly increased 

 when the nature of the problem can be accurately defined. 



There is a school of thought well represented in our large phar- 

 maceutical firms and also in the councils of our government scientific 

 agencies which prefers to advance chemotherapy exclusively by the 

 method of trial-and-error organic synthesis. In effect, the program 

 followed is merely that of permutation and combination of the few 

 effective chemotherapeutic agents we have as models. Instead of 

 looking for new models, the old models are varied over and over again. 

 The very limited success of this program of chemotherapy is hardly 

 surprising. In the first place, not all pharmacologically active sub- 

 stances tolerate any considerable structural change. Thus, no one 

 has been able to prepare a more active form of the vitamin than 

 thiamin. In fact, the slightest alteration of the molecule involves 

 partial or complete loss of activity. The same considerations apply 

 to the vast majority of biologically active substances such as acetyl- 

 choline, histamine, flavin, ascorbic acid, etc. It is certainly true in 

 other instances that a given effect is produced by large numbers of sub- 

 stances sharing a common structure, e. g., adrenalin, and the hundreds 

 of adrenalin-like bases which have been tested, sulfanilamide and the 

 hordes of other sulfa drugs, etc. But one must keep the objective 

 clearly in mind. In the case of adrenalin, the analogues merely 

 imitate the adrenalin eff"ect. They accomplish nothing that adrenalin 

 cannot do. Their virtue lies either in their greater stability or in their 

 greater resistance to deterioration in the animal body. All the known 

 sulfa drugs act in exactly the same way, though they are effective at 

 different concentration levels. The same organisms can be inhibited 

 both by the weakest and strongest sulfa drugs provided the weakest is 



