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As the SARS-CoV-2 pandemic spread throughout the world, universities were faced with extraordinary challenges. Shelter-in-place orders were given, in-person classes were canceled, and at the University of California Irvine, instructors had less than 2 weeks to convert spring quarter classes from a face-to-face to an online format. A team-based approach was essential to making this transition. The insights gained during the design and implementation of the final quarter of a large-enrollment online organic chemistry class are shared here, as well as student perspectives on the efficacy of key components of the course. The lessons learned during this process will be instrumental when converting other face-to-face courses into effective online formats, as online classes continue in the fall.

Supporting Table Table S1. Crystallographic properties, crystallization conditions, and data collection and model refinement statistics for peptide 1. S2 Materials and Methods General information. S3 Synthesis of peptide 1. S3 Crystallization procedure for peptide 1. S5 X-ray crystallographic data collection, data processing, and structure determination for peptide 1. S6 Preparation of Aβ 40 and Aβ 42 oligomers S7 SDS-PAGE and silver staining. S8 Replica exchange molecular dynamics (REMD). S9 References and Notes S10

Oligomers of the β-amyloid peptide, Aβ, play a central role in the pathogenesis and progression of Alzheimer’s disease. Trimers and higher-order oligomers composed of trimers are thought to be the most neurotoxic Aβ oligomers. To gain insights into the structure and assembly of Aβ oligomers, our laboratory has previously designed and synthesized macrocyclic peptides derived from Aβ17–23 and Aβ30–36 that fold to form β-hairpins and assemble to form trimers. In this study, we found that mutating Phe20 to cyclohexylalanine (Cha) in macrocyclic Aβ-derived peptides promotes crystallization of an Aβ-derived peptide containing the Aβ24–29 loop (peptide 3 F20Cha ) and permits elucidation of its structure and assembly by X-ray crystallography. X-ray crystallography shows that peptide 3 F20Cha forms a hexamer. X-ray crystallography and SDS-PAGE further show that trimer 4 F20Cha , a covalently stabilized trimer derived from peptide 3 F20Cha , forms a dodecamer. Size exclusion chromatography shows that trimer 4 F20Cha forms higher-order assemblies in solution. Trimer 4 F20Cha exhibits cytotoxicity against the neuroblastoma cell line SH-SY5Y. These studies demonstrate the use of the F20Cha mutation to further stabilize oligomers of Aβ-derived peptides that contain more of the native sequence and thus better mimic the oligomers formed by full-length Aβ.

This paper presents the design and study of a first-in-class cyclic peptide inhibitor against the SARS-CoV-2 main protease (Mpro). The cyclic peptide inhibitor is designed to mimic the conformation of a substrate at a C-terminal autolytic cleavage site of Mpro. Synthesis and evaluation of a first-generation cyclic peptide inhibitor reveals that the inhibitor is active against Mpro in vitro and is non-toxic toward human cells in culture. The initial hit described in this manuscript, UCI-1, lays the groundwork for the development of additional cyclic peptide inhibitors against Mpro with improved activities.