New molecules offer hope for treating HIV and cancer

Sometimes big things come in small packages. That’s certainly the case for two small molecules created by an international team of researchers that might potentially be developed into treatments for a range of viruses, including HIV, and for certain types of cancers.

The team was led by Professor Volker Haucke of the Freie Universität Berlin, along with Professor Adam McCluskey from the University of Newcastle and Professor Phil Robinson of the Children’s Medical Research Institute.

Read more about Phil Robinson and Adam McCluskey's research.

The three, along with their respective teams, designed two molecules that block the key process of endocytosis, where cells allow molecules to penetrate their protective cell wall and enter the interior.

This process is crucial for allowing everything from signalling hormones to nutrients into the cell, but it can also be hijacked by viruses, such as HIV.

Endocytosis has been studied extensively in the past, but not at the molecular level in order to determine the role of key proteins in the process, such as one called clathrin.

The three came together to try to gain a greater understanding of this process after a conversation between Robinson and Haucke at an editorial meeting for the Journal of Biological Chemistry.

“Volker said ‘I’m interested in endocytosis inhibitors’,” Robinson told ALS. “I said: ‘so am I’. So we started talking about the problems of creating small molecule tools, and the key problem is medicinal chemistry to refine and whip them into shape.”

Volker had already screened 17,000 small molecules from a molecule database and found a handful that appeared to block endocytosis in a test tube, but weren’t potent enough to do so in living cells.

“So I said to Volker: ‘this is where we need Adam McCluskey’. He’s the best medicinal chemist I know of in the world,” said Robinson.

“He just looked at the molecules. That’s it. Just looked at them. And then he designed from scratch, without a computer, two whole new series.

“He made a couple of hundred and we screened those, and they were much more potent in test tube, and they worked in cell culture. Then Volker showed that they hit the target we were aiming in the first place.

“It just didn’t stop going ‘yes, yes, yes’ from that point on.”

The two molecules, which prevent the characteristic ‘pits’ from forming in the cell wall through the process of endocytosis, are called pitstop 1 and pitstop 2.

While each are slightly different, they both fit into the same groove on clathrin and cause it to function in different ways.

One finding that proved exciting was that pitstop 2, in particular, blocked the entry of HIV into the cell.

This proved that HIV actually does hijack the clathrin mediated endocytosis (CME) pathway to enter the cell, something previous studies had hinted at but not confirmed.

This raises the prospect of using pitstop 2 to block this particular endocytosis pathway, potentially preventing infection by HIV and other viruses that use CME, such as ebola and Dengue virus.

A drug that inhibited this pathway, without blocking it completely, would potentially restrict infection by these viruses but would still allow cells to get the required hormones and nutrients, said Robinson.

The two molecules also raise the prospect of treating certain types of cancers, an idea not covered as a part of this paper but which is the focus of ongoing research.

According to Robinson, inhibiting clathrin might prevent some types of cancer from receiving sufficient nutrients to grow and divide out of control while not affecting healthy cells.

It might also inhibit clathrin’s second role in mitosis, which could prevent cancer cells from dividing.

The next step is to fine tune these molecules and go through the pharmacological process of turning them into effective drugs that achieve the desired outcomes without eliciting any deleterious side effects – a process that could take up to a decade or more.

The paper was published today in Cell.