Hitchhiking HIV Drugs Can Cause Negative Side Effects

Researchers reveal how anti-HIV inhibitors bind to the wrong target.

Most individuals taking a medication are all too familiar with negative side effects that can occur while trying to manage or cure HIV.

In a new study published in Nature Chemistry, researchers identified how anti-HIV protein inhibitor drugs can bind to the wrong target and result in these adverse side effects. Researchers used mass spectrometry to directly examine how the drugs link to the wrong protein.

“The ‘hitchhiking’ of drugs on incorrect targets is a common problem but isn’t much studies, as it can be difficult to observe directly,” said corresponding study author Professor Dame Carol Robinson. “You have to know which proteins to look for, and only then can you target these proteins for further research.”

The findings revealed that a series of anti-HIV protein inhibitor drugs called lopinavir, ritonavir, and amprenavir could block the processing of the protein prelamin A.

“The results of this study surprised us, as the drugs target HIV proteases and were not thought to bind the human metalloprotease that is involved in processing prelamin A,” Robinson said.

Prelamin A is essential to maintain the shape of human cells, and is directly related to aging.

“The association between some anti-HIV drugs and premature aging has been suspected for some time through observation of patients undergoing treatment, but it hasn’t been proved at the molecular level,” Robinson said. “There have also been other highly publicized drugs with off-target protein side effects, including an anti-diabetes drug that caused heart attacks in some patients.

“Now that we have developed this mass spectrometry-based approach, we anticipate that it will have widespread application, since it is likely that many drugs that are designed with a specific target in mind end up hitchhiking on other protein targets. It could even be used during the drug development process to determine if drugs are binding to the wrong targets at the molecular level.”