New Approach Allows Insight Into What Happens When Drugs Do Not Work as Expected

A new study led by researchers at the University of Oxford has offered insight into what happens when pharmaceutical drugs do not work as expected. The researchers showed how drugs designed to battle HIV proteins interfere with a protein called prelamin A, a protein that is associated with ageing as well as human cell shape retention.

Sometimes pharmaceutical drugs that are developed to intervene and assist in the fight against infectious diseases are not successful. When this happens, they can cause adverse side effects, which are unwanted and sometimes harmful reactions. Although this is a “well-known phenomenon,” according to the official press release, there has been little research conducted when it comes to examining the process that occurs when drugs do not carry out their intended purpose.

According to the study, the researchers used high resolution mass spectrometry, an analytical technique that measures the mass of molecules as a way to identify them. The technique allowed the researchers to examine how anti-HIV protein inhibitor drugs “hitchhik[ed]” onto the wrong target protein. An author of the paper, Professor Dame Carol Robinson of Oxford’s Department of Chemistry, said, “The ‘hitchhiking’ of drugs on incorrect targets is a common problem but isn’t much studied, as it can be difficult to observe directly. You have to know which proteins to look for, and only then can you target these proteins for further research.”

When discussing the results, Professor Robinson added, “The results of the 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.”

The researchers made an interesting discovery: the pharmaceutical drugs ritonavir, lopinavir, and amprenavir that are used to battle HIV, also prevented prelamin A from being processed.

When speaking of the implications of this discovery, Professor Robinson said, “The association between some anti-HIV drugs and premature ageing has been suspected for some time through observation of patients undergoing treatment, but it hasn’t been proved at the molecular level. 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.”

Due to the fact that there are many pharmaceutical drugs that end up “hitchhiking” onto proteins, the researchers at the University of Oxford anticipate that there will be widespread use of the mass-spectrometry-based approach that they used within their study during the process of a drug’s development. With this approach, drug developers are provided with the means to directly observe the functionality of the drug and will be able to see if it is binding to the wrong targets.