Always more to yield: unanswered questions in chemistry II

In 2008, a team of researchers busily excavated the tiny (only 55m²) coastal Blombos Cave, 300 km east of Cape Town, South Africa, when they discovered something entirely unexpected: a workshop, dating back some 100,000 years, where liquefied ochre-rich mixture was made and stored.

This processing workshop is evidence that humans had some rudimentary knowledge of chemistry even as far back as the stone age.

Since then, chemistry has spawned multiple sub-disciplines, from biochemistry (the study of matter and their interactions and reactions in living organisms) to astrochemistry (the study of matter in the Universe), including their reactions and interactions.

Chemistry abounds in discoveries, but many questions remain. We asked members of the Canadian Journal of Chemistry’s International Advisory Board: What’s the most important unanswered question in your field?

Janet Macdonald | Crystal interactions

At Vanderbilt University in Tennessee, USA, Professor Janet Macdonald is researching the synthesis of nanocrystals and, in particular, transition metal chalcogenides. “Since these are essentially tiny rocks, I like to joke and call myself a nano-inorganic natural product chemist,” says MacDonald.

If you look at a periodic table, you’ll find the transition metal group sitting right in the middle. Most metals are transition metals, including those we are most familiar with, like iron, gold, and nickel. When transition metals are combined with an element from the oxygen family (chalcogenides), transition metal chalcogenides are born.

“I think we had assumed that everything was already in the geologic record, but even for simple binaries like copper and selenium, nanocrystal chemistry has some tricks up her sleeve!” says MacDonald.

Synthetic nanocrystals have many different applications, including the development of solar energy systems.

“Semiconductor nanocrystals have long been identified as potentially revolutionary light-absorbing materials in green energy applications like solar cells and solar-to-fuel technologies,” MacDonald explains. “We have had several projects that look at designing, very carefully, the surface chemistry of nanocrystals to improve charge transfer, including one where we collaborated with Edward Sargent’s group at the University of Toronto.”

A key question that MacDonald would like answered: What exactly happens when ligands—an atom or molecule that is attached to a central (typically metallic) atom—interact with the surface of synthetic nanocrystals?

Annika Möslein | Metal-organic framework materials (ZIF-8, crystal size ~100nm), an emergent class of hybrid, porous nanomaterials.

“There is no easy characterisation technique to get a clear molecular image of these interactions, so our knowledge of surfaces is often through indirect characterisation and supposition,” explains MacDonald.

“Understanding what happens at the surface could help develop new synthetic nanocrystals. These interactions are controlling the size, the shape and even the crystalline phase of the nanocrystals, but they ultimately also control function whether it be catalysis, fluorescence yields, or where they end up in cells,” says MacDonald.

Paul Thompson |  Pocketless proteins

Nearly 1700km away at the University of Massachusetts, Professor Paul Thompson’s work is seeking to improve human health. Thompson uses chemical biology for pharmacological applications such as chemical probes—small molecule tools that can help researchers target proteins inside cells and tissues and learn more about their role in disease.

“Developing chemical probes for novel targets [new ways to combat disease] is incredibly exciting because such probes can unlock new biology and hold the potential to be therapeutics for a range of different diseases,” Thompson explains.

The research Thompson and his team are conducting has led to developing several compounds that are being evaluated in preclinical models of diseases such as lupus, diabetes, and rheumatoid arthritis.

Given their use in how we study and understand disease, “[c]hemical probes need to fulfil stringent criteria to qualify as research tools.” eLife 2018;7:e34311 DOI: 10.7554/eLife.34311

The team has also been working on treating SARS-CoV2 by targeting the virus’ main protease—an enzyme that plays a crucial role in a virus’s life cycle. The researchers hope that if they can block the main protease from functioning, the virus will no longer be able to replicate itself.

“I believe that a key challenge remains the development of novel therapeutics for proteins that lack the defined pockets that are characteristic of enzymes and receptors,” says Thompson.

In essence, “pockets”’ are tiny grooves where molecules or other substrates bind and create a chemical reaction. Also known as active sites, it is here where drugs normally can target and attack disease.

Thompson thinks “new proteolysis-based strategies [which break down proteins into peptides or amino acids] hold the promise of addressing this unmet need.”

Don’t miss out on unanswered questions about porphyrins and inorganic clusters in part I of this series.