A High-Throughput Screening Pipeline to Identify Methyltransferase and Exonuclease Inhibitors of SARS-CoV-2 NSP14.

SARS-CoV-2 infections led to a worldwide pandemic in 2020. As of 2024, therapeutics against SARS-CoV-2 have continued to be desirable. NSP14 is a dual-function methyltransferase (MTase) and exonuclease (ExoN) with key roles in SARS-CoV-2 genome propagation and host immune system evasion.

Target Class Profiling of Small-Molecule Methyltransferases.

Target class profiling (TCP) is a chemical biology approach to investigate understudied biological target classes. TCP is achieved by developing a generalizable assay platform and screening curated compound libraries to interrogate the chemical biological space of members of an enzyme family. In this work, we took a TCP approach to investigate inhibitory activity across a set of small-molecule methyltransferases (SMMTases), a subclass of methyltransferase enzymes, with the goal of creating a launchpad to explore this largely understudied target class.

A humanized nanobody phage display library yields potent binders of SARS CoV-2 spike.

Neutralizing antibodies targeting the SARS-CoV-2 spike protein have shown a great preventative/therapeutic potential. Here, we report a rapid and efficient strategy for the development and design of SARS-CoV-2 neutralizing humanized nanobody constructs with sub-nanomolar affinities and nanomolar potencies. CryoEM-based structural analysis of the nanobodies in complex with spike revealed two distinct binding modes.

A humanized nanobody phage display library yields potent binders of SARS CoV-2 spike.

Neutralizing antibodies targeting the SARS-CoV-2 spike protein have shown a great preventative/therapeutic potential. Here, we report a rapid and efficient strategy for the development and design of SARS-CoV-2 neutralizing humanized nanobody constructs with sub-nanomolar affinities and nanomolar potencies. CryoEM-based structural analysis of the nanobodies in complex with spike revealed two distinct binding modes.

Hybrid Approach Reveals Novel Inhibitors of Multiple SARS-CoV-2 Variants.

The National Center for Advancing Translational Sciences (NCATS) has been actively generating SARS-CoV-2 high-throughput screening data and disseminates it through the OpenData Portal (https://opendata.ncats.nih.

Targeting ACE2-RBD Interaction as a Platform for COVID-19 Therapeutics: Development and Drug-Repurposing Screen of an AlphaLISA Proximity Assay.

The COVID-19 pandemic, caused by SARS-CoV-2, is a pressing public health emergency garnering a rapid response from scientists across the globe. Host cell invasion is initiated through direct binding of the viral spike protein to the host receptor angiotensin-converting enzyme 2 (ACE2). Disrupting the spike protein-ACE2 interaction is a potential therapeutic target for treating COVID-19.

Targeting ACE2-RBD interaction as a platform for COVID19 therapeutics: Development and drug repurposing screen of an AlphaLISA proximity assay.

The COVID-19 pandemic, caused by SARS-CoV-2, is a pressing public health emergency garnering rapid response from scientists across the globe. Host cell invasion is initiated through direct binding of the viral spike protein to the host receptor angiotensin-converting enzyme 2 (ACE2). Disrupting the spike-ACE2 interaction is a potential therapeutic target for treating COVID-19.

An OpenData portal to share COVID-19 drug repurposing data in real time.

The National Center for Advancing Translational Sciences (NCATS) has developed an online open science data portal for its COVID-19 drug repurposing campaign - named OpenData - with the goal of making data across a range of SARS-CoV-2 related assays available in real-time. The assays developed cover a wide spectrum of the SARS-CoV-2 life cycle, including both viral and human (host) targets. In total, over 10,000 compounds are being tested in full concentration-response ranges from across multiple annotated small molecule libraries, including approved drug, repurposing candidates and experimental therapeutics designed to modulate a wide range of cellular targets.

Calmodulin-induced Conformational Control and Allostery Underlying Neuronal Nitric Oxide Synthase Activation.

Nitric oxide synthase (NOS) is the primary generator of nitric oxide signals controlling diverse physiological processes such as neurotransmission and vasodilation. NOS activation is contingent on Ca/calmodulin binding at a linker between its oxygenase and reductase domains to induce large conformational changes that orchestrate inter-domain electron transfer. However, the structural dynamics underlying activation of full-length NOS remain ambiguous.

A perspective on the structure and receptor binding properties of immunoglobulin G Fc.

Recombinant antibodies spurred a revolution in medicine that saw the introduction of powerful therapeutics for treating a wide range of diseases, from cancers to autoimmune disorders and transplant rejection, with more applications looming on the horizon. Many of these therapeutic monoclonal antibodies (mAbs) are based on human immunoglobulin G1 (IgG1) or contain at least a portion of the molecule. Most mAbs require interactions with cell surface receptors for efficacy, including the Fc γ receptors.

Restricted motion of the conserved immunoglobulin G1 N-glycan is essential for efficient FcγRIIIa binding.

Immunoglobulin G1 (IgG1)-based therapies are widespread, and many function through interactions with low-affinity Fc γ receptors (FcγR). N-glycosylation of the IgG1 Fc domain is required for FcγR binding, though it is unclear why. Structures of the FcγR:Fc complex fail to explain this because the FcγR polypeptide does not bind the N-glycan.