We developed a de novo protein design strategy to swiftly engineer decoys for neutralizing pathogens that exploit extracellular host proteins to infect the cell. Our pipeline allowed the design, validation, and optimization of de novo hACE2 decoys to neutralize SARS-CoV-2. The best decoy, CTC-445.2, binds with low nanomolar affinity and high specificity to the RBD of the spike protein. Cryo-EM shows that the design is accurate and can simultaneously bind to all three RBDs of a single spike protein. Because the decoy replicates the spike protein target interface in hACE2, it is intrinsically resilient to viral mutational escape. A bivalent decoy, CTC-445.2d, shows ~10-fold improvement in binding. CTC-445.2d potently neutralizes SARS-CoV-2 infection of cells in vitro and a single intranasal prophylactic dose of decoy protected Syrian hamsters from a subsequent lethal SARS-CoV-2 challenge.

No abstract

II.

Search indices are fundamental building blocks of many systems, and there is great interest in running them on encrypted data. Unfortunately, many known schemes that enable search queries on encrypted data achieve efficiency at the expense of security, as they reveal access patterns to the encrypted data.In this paper we present Oblix, a search index for encrypted data that is oblivious (provably hides access patterns), is dynamic (supports inserts and deletes), and has good efficiency.Oblix relies on a combination of novel oblivious-access techniques and recent hardware enclave platforms (e.g., Intel SGX). In particular, a key technical contribution is the design and implementation of doubly-oblivious data structures, in which the client's accesses to its internal memory are oblivious, in addition to accesses to its external memory at the server. These algorithms are motivated by hardware enclaves like SGX, which leak access patterns to both internal and external memory.We demonstrate the usefulness of Oblix in several applications: private contact discovery for Signal, private retrieval of public keys for Key Transparency, and searchable encryption that hides access patterns and result sizes.