WIM no. 17 Spring 2020

מכון ויצמן למדע 6–7 S P R I N G 2 0 2 0 Designing the perfect antibody Prof. Sarel Fleishman is applying computer modeling tools to create a coronavirus-blocking solution P rof. Sarel Fleishman and his team in the Department of Biomolecular Sciences are using a unique platform developed in their lab 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 they home in on the most effective nanobodies, it may become possible to design a treatment capable of stopping the deadly virus. A structural biologist and technology innovator, Prof. Fleishman has developed computer modeling tools that support the rapid and inexpensive design of customized proteins. Much of his work focuses on antibodies—proteins that defend the body against disease-causing invaders, like viruses and bacteria. Now, 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. The lab invented a methodology to design computer-based models of proteins, including antibodies, that do not exist in nature, and which have superior properties. The tools—available online and used by labs around the world—encode how proteins fold and function and 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 an 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 for impoverished populations living in tropical climates. Successfully tested in laboratory studies by Prof. Fleishman’s colleagues in the UK, the new proteins 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. That’s 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 will massively expand a computational protocol already validated on a small scale in his lab. His 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, and winnow down the set using experimental high-throughput screening technology, thereby identifying the top antibody candidates. g Prof. Sarel Fleishman’s method has been proven in the development of a potential malaria vacccine. Video: Prof. Sarel Fleishman: Designing a coronavirus vaccine Weizmann MAGAZINE