An off-​​switch for drugs’ toxic side effects

When med­ica­tions linger in the human body, they some­times pro­duce toxic side effects.

Pro­fessor Alexan­dros Makriyannis, the George D. Behrakis Trustee Chair in Phar­ma­ceu­tical Biotech­nology and Director of the Center for Drug Dis­covery at North­eastern, explained that many things can happen to a drug inside our bodies once it is ingested. For instance, the drug can be mod­i­fied into other byprod­ucts with their own unde­sir­able and unpre­dictable effects. Or it can remain embedded in the body’s fatty tis­sues and then be slowly released into the cir­cu­la­tory system.

“If you had a way of con­trol­ling how long this drug sits in the body,” Makriyannis said, “that would be a ben­e­fi­cial effect. It would be a safer drug.”

In research recently pub­lished in the Journal of Med­i­c­inal Chem­istry and Med­i­c­inal Chem­istry Let­ters, Makriyannis and his team present not just one such drug but a whole series of them. “We call this con­cept con­trolled deac­ti­va­tion,” he explained.

In this research, Makriyannis’ team presents more than 100 com­pounds that are vari­ants of drugs the researchers pre­vi­ously patented. These new drugs target the endo­cannabi­noid system, which includes recep­tors within the sur­face of cells throughout our bodies that are respon­sible for func­tions like pain, mood, memory, and appetite modulation.

The orig­inal ver­sions of the new drugs bind to the cannabi­noid receptors—which were ini­tially named for their recog­ni­tion of the tetrahy­dro­cannabinol mol­e­cule found in marijuana—and pro­duce some effects such as increased appetite or a sense of euphoria. How­ever, the devel­op­ment of these drugs has been lim­ited by the neg­a­tive side effects they elicit. In one high-​​profile case, a cannabi­noid antag­o­nist called Acom­plia was designed to pro­duce the oppo­site effects of cannabis. The drug was intended to treat obe­sity, but was pulled from the market when it was linked to increased sui­cide rates.

“Our lab works to design and make safer drugs with more con­trol­lable action,” Makriyannis said. So with funding from the National Insti­tute on Drug Abuse, he and his team set out to develop drugs that fea­ture a timing mech­a­nism that would allow the drug to be deac­ti­vated as soon as it has per­formed its func­tion and be trans­formed to inac­tive products.

This timing mech­a­nism, Makriyannis said, is rel­a­tively simple—it just takes some very smart and spe­cific chemistry.

The new drugs are chem­i­cally mod­i­fied to be biodegrad­able and sus­cep­tible to par­tic­ular enzymes in the blood. The enzymes would rec­og­nize these drug’s new chem­ical fea­tures and “chew them up” right at that spot. The time it takes for the enzymes to finish their action can be con­trolled, and the resulting byprod­ucts from this enzy­matic activity are com­pletely safe, according to Makriyannis.

Addi­tion­ally, the drugs’ chem­ical mod­i­fi­ca­tions ensure they don’t stick around in the body’s fatty tis­sues as long, and are thus expelled much more quickly.

“When we started making these new com­pounds, we weren’t sure if they would be suc­cessful,” Makriyannis said. “But actu­ally, they worked even better than we’d hoped.” Not only do the com­pounds have fewer side effects than the orig­inal ver­sions of the drugs, they are also more potent and effective.

While the drugs in the present research all target recep­tors in the endo­cannabi­noid system, the approach can be applied to vir­tu­ally any small-​​molecule drug, Makriyannis said.

“We are con­trol­ling the fate of a drug by just designing these mol­e­cules in a manner that allows them to act pre­dictably,” he said. “It’s a gen­eral con­cept that we’ve used to make anal­gesic com­pounds that are safer and very potent, but the same con­cept could be used to make neu­ro­pro­tec­tive drugs or other ther­a­peutic agents.”

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