Report of the National Institutes of Health SARS-CoV-2 Antiviral Therapeutics Summit

The NIH Virtual SARS-CoV-2 Antiviral Summit, held on 6 November 2020, was organized to provide an overview on the status and challenges in developing antiviral therapeutics for coronavirus disease 2019 (COVID-19), including combinations of antivirals. Scientific experts from the public and private sectors convened virtually during a live videocast to discuss severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) targets for drug discovery as well as the preclinical tools needed to develop and evaluate effective small-molecule antivirals. The goals of the Summit were to review the current state of the science, identify unmet research needs, share insights and lessons learned from treating other infectious diseases, identify opportunities for public-private partnerships, and assist the research community in designing and developing antiviral therapeutics. This report includes an overview of therapeutic approaches, individual panel summaries, and a summary of the discussions and perspectives on the challenges ahead for antiviral development

Bridging the Gap to Translating Genomewide Discoveries into Therapies to Prevent and Treat Atherosclerotic Cardiovascular Disease

The authors provide a review article that comments on a peer-reviewed article to be published in the journal Circulation: "Solomon CU, McVey DG, Andreadi C, Gong P, Turner L, Stanczyk PJ, Khemiri S, Chamberlain JC, Yang W, Webb TR, Nelson CP, Samani NJ, Ye S. Effects of coronary artery disease-associated variants on vascular smooth muscle cells." Comments include a brief overiview of the field of genomics (genomewide association studies=GWAS) of CAD, summary of the "Solomon et al" study findings, strengths and limitations of the "Solomon et al" study, and opportunities and gaps for drug development for prevention and treatment of CAD

Synthetic Transcription Elongation Factors license transcription across repressive heterochromatin

Switching a paused RNA polymerase II into productive elongation is tightly-regulated, especially at genes involved in human development and disease. To exert control on this rate-limiting step, we designed sequence-specific synthetic transcription elongation factors (Syn-TEFs). These molecules are composed of programmable DNA-binding ligands flexibly tethered to a small molecule that binds a component of the transcription elongation machinery. The resultant bifunctional molecules convert constituent modules from broad-spectrum inhibitors of transcription into a gene-specific stimulator of transcriptional elongation. Here, we present Syn-TEF1, a molecule that actively facilitates transcription across repressive GAA repeats that silence frataxin expression in Friedreich’s ataxia, a debilitating and ultimately lethal neurodegenerative disease with no effective therapy. Our modular design provides a framework for generating a class of molecules that license transcription elongation at targeted genomic loci

An IMiD-inducible degron provides reversible regulation for chimeric antigen receptor expression and activity

The recent development of successful CAR (chimeric antigen receptor) T cell therapies has been accompanied by a need to better control potentially fatal toxicities that can arise from adverse immune reactions. Here we present a ligand-controlled CAR system, based on the IKZF3 ZF2 β-hairpin IMiD-inducible degron, which allows for the reversible control of expression levels of type I membrane proteins, including CARs. Testing this system in an established mouse xenotransplantation model for acute lymphoblastic leukemia, we validate the ability of the CAR19-degron to target and kill CD19-positive cells displaying complete control/clearance of the tumor. We also demonstrate that the activity of CAR19-degron can be regulated in vivo when dosing a US Food and Drug Administration-approved drug, lenalidomide