Interview with Prof. Michael Lawrence Klein

Michael Lawrence Klein is Carnell Professor of Science and Dean of Science and Technology, at Temple University, Philadelphia, USA. He was Hepburn Professor of Physical Science and director, Lab. for Research on the Structure of Matter, Univ. of Pennsylvania (UPenn), Philadelphia. After his PhD (Univ. of Bristol) and postdoctoral work in Italy, England, and USA, he joined the National Research Council of Canada. In 1987, he joined UPenn where he established the Center for Molecular Modeling. He is member of the National Academy of Sciences of the USA, a Fellow of: Royal Society of London; Royal Society of Canada; and American Academy of Arts and Sciences. Awards include: American Physical Society Aneesur Rahman Prize for Computational Physics; American Chemical Society Debye Award in Physical Chemistry; and Bernie J. Alder CECAM Prize, European Physical Society.

In an interview to Vanita Srivastava, Prof. Klein talks about his research just before the Institute Lectuture.

What is the research that you are doing?

I continue to be interested in cell-wall membrane-bound ion channels, and especially those that have a role in sensing. The protein that binds chili pepper, is called TRPV1, and it does more than just tell us that chili is a "hot" spice. This protein also senses acidity and temperature. My research focus is on how this particular nano-scale machine from Nature actually works.

Can you elaborate a bit on TRPV1?

The transient receptor potential cation channel, subfamily V member 1 (TRPV1) or vanilloid receptor 1 is a nonselective cation channel that is involved in the detection and transduction of nociceptive stimuli. Inflammation and nerve damage result in the up-regulation of TRPV1 transcription, and, therefore, modulators of TRPV1 channels are potentially useful in the treatment of inflammatory and neuropathic pain. Understanding the binding modes of known ligands would potentially significantly contribute to the success of TRPV1 modulator drug design programs. The recent cryo-electron microscopy structure of TRPV1 only provides a coarse characterization of the location of capsaicin (CAPS) and resiniferatoxin (RTX). In research from my group, we use the information contained in the experimental electron density maps to accurately determine the binding mode of CAPS and RTX and experimentally validate the computational results by mutagenesis experiments. On the basis of these results, we performed a detailed analysis of TRPV1–ligand interactions, characterizing the protein ligand contacts and the role of individual water molecules. Importantly, our results provide a rational explanation and suggestion of TRPV1 ligand modifications that should improve binding affinity. This work is continuing at the present time.

Can you a elucidate on your research on how a drug used in the treatment of HIV can suppress Zika virus infection?

Rilpivirine is one of several non-nucleoside reverse transcriptase inhibitor (NNRTI) drugs that have been developed for the treatment of HIV infection. Collaborators in the Temple’s Katz Schoolof Medicine tested this and two other NNRTIs in Zika-infected cells to explore effects on viral replication. In cell and animal models, they showed that Rilpivirine stops Zika virus by targeting enzymes that both HIV and Zika virus depend on for their replication. Computational studies from my group explained the mode of action of Rilpivirine. Since similar enzymes occur in other viruses closely related to Zika, including the viruses that cause dengue, yellow fever, West Nile fever, and hepatitis C, our findings suggest there is much potential for developing cost-effective treatments for all of these debilitating diseases.

4th December 2019