Designing a solution
Computational approach may lead to a future treatment for coronavirus
As the coronavirus pandemic spreads, Prof. Sarel Fleishman and his team in the Department of Biomolecular Sciences are deep into planning mode. Using a unique platform developed in their lab, they seek to address the coronavirus problem by designing and testing millions of “nanobodies”—small synthetic antibodies that could potentially slip through the coronavirus’s formidable defenses. Once the scientists home-in on the most effective nanobodies, it may become possible to design a treatment capable of stopping the deadly virus which has already claimed thousands of lives worldwide.
A structural biologist and technology innovator, Prof. Fleishman is the developer of computer modeling tools that support the rapid and inexpensive design of customized proteins that have desirable properties. Much of his design work focuses on antibodies—proteins that defend the body against disease-causing invaders, like viruses and bacteria. In the current crisis, he is focused on a particular structural element in the coronavirus—the “spike protein” recently characterized by scientists at the University of Texas in Austin which plays a key role in the infection process. His goal is to design a robust antibody that would bind to vulnerable points on the spike protein and stop infection in its tracks.
Lessons from malaria
The potential impact of this design approach is illustrated by a recent breakthrough achieved in the Fleishman lab against another infectious killer: the parasite Plasmodium falciparum which causes malaria.
Prof. Fleishman’s lab invented of a methodology that makes it possible to design computer-based models of proteins, including antibodies, that do not exist in nature, and which have superior properties. The tools—which are available online and are used by labs around the world—encode the current understanding of how proteins fold and function. These tools also predict how specific mutations would impact protein characteristics on the atomic level.
Two years ago, an algorithm created by Dr. Adi Goldenzweig—then a PhD student in the Fleishman lab—resulted in the design of a superior anti-malarial vaccine. Not only did these synthetic proteins provoke a protective immune response that short-circuited infection by the malaria parasite, they were also cost-effective to produce, and remained stable at extremely high temperatures—a significant advantage in a vaccine designed mainly for impoverished populations living in tropical climates. Successfully tested in laboratory studies by Prof. Fleishman’s colleagues in the UK, the new proteins show great promise for similar success in the field and are being scaled up for release as a commercial vaccine.
Antibodies that are perfectly primed to block coronavirus will not be easy to design, however. This is because the spike protein structures that drive infection are shielded by particularly complex structures known as glycans. To get past this glycan shield, Prof. Fleishman plans to massively expand a computational protocol already validated on a small scale in his lab.
Using the Weizmann Institute’s infrastructure for high-performance computing, the team, comprising doctoral student Lucas Krauss, and Drs. Ravit Netzer and Adi Goldenzweig, are leveraging their suite of protein design tools to generate computer models of millions of designed antibodies in search of those most likely to bind successfully to one or more of the coronavirus’s vulnerable sites. The lab will then synthesize these millions of designed antibodies —in itself, a challenging feat enabled by recent methods developed in the lab—and then winnow down this massive set using experimental high-throughput screening technology, thereby identifying the top antibody candidates.
The “finalists” will be tested for their ability to neutralize infective coronavirus samples—something that may lay the ground for a future treatment for COVID-19, and aid in vaccine development.
Prof. Sarel-Jacob Fleishman is the Head of the Dr. Barry Sherman Institute for Medicinal Chemistry. He is supported by the Yeda-Sela Center for Basic Research, the Schwartz/Reisman Collaborative Science Program, Edmond de Rothschild Foundations, the Henri Gutwirth Fund for Research, Sam (Ousher) Switzer & Children, Dianne and Irving Kipnes Foundation, Carolyn Hewitt and Anne Christopoulos, in Memory of Sam Switzer, Darlene Switzer-Foster and Bill Foster, Susan and Michael Stern, Stanley and Ellen Magidson, and the European Research Council.