Tweezer standing

Where did the Molecular Tweezers come from?

Molecular tweezers- What does that mean? What are they? How did they become drug candidates for degenerative diseases?

The story of the molecular tweezers is a great example of the way science works – step-by-step, layer-by-layer, with each one being built on the foundation of the previous one.

The molecular tweezers are the brainchild of Frank-Gerrit Klärner, Professor Emeritus of Organic Chemistry at the University of Duisburg-Essen in Germany. They were designed as chemical “hosts” for smaller “guest” molecules. The original paper by Klärner and his colleagues was published in 1996 in the prestigious chemistry journal Angewandte Chemie International Edition in English:


The tweezers are special molecules that have a horseshoe shape. The ability of these molecules to include “guests” inside the horseshoe structure reminded Klärner and his co-worker of tweezers holding a small particle or a hair, and therefore they named them molecular tweezers.

In their original work, the scientists discovered that straight hydrocarbon chains were the preferred “guests” inside the cavity of the molecular tweezers. This was very important for the next layer to be laid in the scientific discovery.

In the next step, Professor Klärner collaborated with Thomas Schrader, then at the University of Marburg, Germany, and today also Professor of Organic at the University of Duisburg-Essen. Together, the research groups of Professors Klärner and Schrader introduced chemical changes in the structure of the tweezers that for the first time made them water-soluble. Now, instead of simple hydrocarbon chains, which are oily in nature, they could test as guests molecules that also were water-soluble, opening the door for biological applications. They found that the preferred “guests” of the water-soluble tweezers were derivatives that contained an ammonium group, which is an important component of amino acids and other biological molecules.

Based on these findings, Professor Schrader decided to investigate the tweezers as potential hosts, or as they were described later – “artificial receptors,” for amino acids. The investigation led to the discovery that the tweezers bounds with high selectivity to the amino acid Lysine. This discovery was published in 2005, in the Journal of the American Chemical Society:



In the first few months of 2005, 5,670 miles south-east of Essen, Gal Bitan, then a new Assistant Professor at UCLA, was busy thinking about a discovery made by Professor David Teplow, also at UCLA, and then postdoctoral fellow, Dr. Noel Lazo (today an Associate Professor at Clark University, Worcester, MA, USA). Drs. Teplow and Lazo had just published a paper in the journal Protein Science where they reported that a particular structure in the protein believed to cause Alzheimer’s disease, beta-amyloid, was the key to the transition of this protein from a regular component of every cell’s normal biological function, to a toxin that kills brain cells and causes dementia [1]. The key to the formation of this dangerous structure was a lysine in the amino-acid sequence of beta-amyloid. “If only I could find a way to block the molecular interactions of this lysine with the rest of the protein, I may have a lead towards developing therapy for Alzheimer’s disease,” Professor Bitan thought. You can imagine his excitement when he saw the paper shown above by Fokkens, Schrader, and Klärner.

The Bitan research group got samples of several molecular tweezers from Professor Schrader and began testing them. To their delight, the tweezers worked just as they expected and blocked the transformation of beta-amyloid from a harmless protein to a vicious toxin. As they continued their research, they realized that due to their unique mechanism of action, the molecular tweezers also had the same effect on many other proteins that cause different diseases. They published their discoveries in 2011, again in the Journal of the American Chemical Society:

Sinha JACS 2011 title

Since then, in collaboration with many research groups around the world, the team has been continuing to study the unique mechanism of action of the molecular tweezers and their therapeutic effects in scientific models of different disease.

The next big discovery came about through collaboration with Professors Jan Münch, Ulm University, Germany, and James Shorter, University of Pennsylvania, Philadelphia, PA, USA, who independently discovered that the molecular tweezers could prevent the enhancement of HIV infection caused by abnormal protein aggregates in semen. These protein aggregates dramatically increase the chances of HIV infection. The experiments of Professors Münch and Shorter showed that the molecular tweezers completely blocked this enhancement effect. But when the two laboratories joined forces, they made an even bigger discovery – they found that the molecular tweezers not only blocked the enhancement of infection but also destroyed an essential component of the viruses themselves — their protective membranes! This was completely unexpected and turned out to be a separate activity from the inhibition of protein aggregation. Moreover, the researchers discovered that this therapeutic activity of the molecular tweezers was not limited to the HIV virus, but was also applicable to many other membrane-encapsulated viruses, such as the hepatitis C and herpes viruses. The findings were published in the prestigious journal eLife in 2015.