Discrete Coiled Coil Rotamers Form within the EGFRvIII Juxtamembrane Domain.

Mutations in the epidermal growth factor receptor (EGFR) extracellular domain (ECD) are implicated in the development of glioblastoma multiforme (GBM), which is a highly aggressive form of brain cancer. Of particular interest to GBM is the EGFR variant known as EGFRvIII, which is distinguished by an in-frame deletion of exons 2-7, which encode ECD residues 6-273. Included within the deleted region is an autoinhibitory tether, whose absence, alongside unique disulfide interactions within the truncated ECD, supports assembly of a constitutively active asymmetric kinase dimer. Previous studies have shown that the binding of growth factors to the ECD of wild-type EGFR leads to the formation of two distinct coiled coil dimers in the cytoplasmic juxtamembrane (JM) segment, whose identities correlate with the downstream phenotype. One coiled coil contains leucine residues at the interhelix interface (EGF-type), whereas the other contains charged and polar side chains (TGF-α-type). It has been proposed that growth-factor-dependent structural changes in the ECD and adjacent transmembrane helix are transduced into distinct JM coiled coils. Here, we show that, in the absence of this growth-factor-induced signal, the JM of EGFRvIII adopts both EGF-type and TGF-α-type structures, providing direct evidence for this hypothesis. These studies confirm that the signals that define JM coiled coil identity begin within the ECD, and support a model in which growth-factor-induced conformational changes are transmitted from the ECD through the transmembrane helix to favor different coiled coil isomers within the JM.

Identification and Development of Therapeutics for COVID-19.

After emerging in China in late 2019, the novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spread worldwide, and as of mid-2021, it remains a significant threat globally. Only a few coronaviruses are known to infect humans, and only two cause infections similar in severity to SARS-CoV-2: Severe acute respiratory syndrome-related coronavirus, a species closely related to SARS-CoV-2 that emerged in 2002, and Middle East respiratory syndrome-related coronavirus, which emerged in 2012. Unlike the current pandemic, previous epidemics were controlled rapidly through public health measures, but the body of research investigating severe acute respiratory syndrome and Middle East respiratory syndrome has proven valuable for identifying approaches to treating and preventing novel coronavirus disease 2019 (COVID-19). Building on this research, the medical and scientific communities have responded rapidly to the COVID-19 crisis and identified many candidate therapeutics. The approaches used to identify candidates fall into four main categories: adaptation of clinical approaches to diseases with related pathologies, adaptation based on virological properties, adaptation based on host response, and data-driven identification (ID) of candidates based on physical properties or on pharmacological compendia. To date, a small number of therapeutics have already been authorized by regulatory agencies such as the Food and Drug Administration (FDA), while most remain under investigation. The scale of the COVID-19 crisis offers a rare opportunity to collect data on the effects of candidate therapeutics. This information provides insight not only into the management of coronavirus diseases but also into the relative success of different approaches to identifying candidate therapeutics against an emerging disease. IMPORTANCE The COVID-19 pandemic is a rapidly evolving crisis. With the worldwide scientific community shifting focus onto the SARS-CoV-2 virus and COVID-19, a large number of possible pharmaceutical approaches for treatment and prevention have been proposed. What was known about each of these potential interventions evolved rapidly throughout 2020 and 2021. This fast-paced area of research provides important insight into how the ongoing pandemic can be managed and also demonstrates the power of interdisciplinary collaboration to rapidly understand a virus and match its characteristics with existing or novel pharmaceuticals. As illustrated by the continued threat of viral epidemics during the current millennium, a rapid and strategic response to emerging viral threats can save lives. In this review, we explore how different modes of identifying candidate therapeutics have borne out during COVID-19.

Identification and Development of Therapeutics for COVID-19.

After emerging in China in late 2019, the novel coronavirus SARS-CoV-2 spread worldwide and as of mid-2021 remains a significant threat globally. Only a few coronaviruses are known to infect humans, and only two cause infections similar in severity to SARS-CoV-2: Severe acute respiratory syndrome-related coronavirus, a closely related species of SARS-CoV-2 that emerged in 2002, and Middle East respiratory syndrome-related coronavirus, which emerged in 2012. Unlike the current pandemic, previous epidemics were controlled rapidly through public health measures, but the body of research investigating severe acute respiratory syndrome and Middle East respiratory syndrome has proven valuable for identifying approaches to treating and preventing novel coronavirus disease 2019 (COVID-19). Building on this research, the medical and scientific communities have responded rapidly to the COVID-19 crisis to identify many candidate therapeutics. The approaches used to identify candidates fall into four main categories: adaptation of clinical approaches to diseases with related pathologies, adaptation based on virological properties, adaptation based on host response, and data-driven identification of candidates based on physical properties or on pharmacological compendia. To date, a small number of therapeutics have already been authorized by regulatory agencies such as the Food and Drug Administration (FDA), while most remain under investigation. The scale of the COVID-19 crisis offers a rare opportunity to collect data on the effects of candidate therapeutics. This information provides insight not only into the management of coronavirus diseases, but also into the relative success of different approaches to identifying candidate therapeutics against an emerging disease.

Retraction of "Targeted Protein Internalization and Degradation by ENDosome TArgeting Chimeras (ENDTACs)".

[This retracts the article DOI: 10.1021/acscentsci.9b00224.].

Targeted Protein Internalization and Degradation by ENDosome TArgeting Chimeras (ENDTACs).

Targeted protein degradation has generated excitement in chemical biology and drug discovery throughout academia and industry. By hijacking the machinery responsible for protein degradation via the ubiquitin proteasome system (UPS), various cellular targets have been selectively degraded. However, since the tools used, often termed PROteolysis TArgeting Chimeras (PROTACs), hijack the intracellular quality control machinery, this technology can only access targets within the cell. Extracellular targets such as growth factors, cytokines, and chemokines bind to cell surface receptors, often initiating aberrant signaling in multiple diseases such as cancer and inflammation. However, efforts to develop small molecule inhibitors for these extracellular target proteins have been challenging. Herein, we developed a proof-of-concept approach to evaluate if extracellular proteins can be internalized and degraded via the receptor-mediated endolysosomal pathway. Using a heterodimeric molecule, termed "ENDosome TArgeting Chimera" (ENDTAC), internalization and degradation of an extracellular recombinant eGFP-HT7 fusion protein was achieved by hijacking the decoy GPCR receptor, CXCR7. This proof-of-concept study suggests that using ENDTACs to co-opt the endosomal-lysosomal degradation pathway, in contrast to PROTACs using the UPS, may provide an avenue for degrading extracellular targets such as cytokines. Overall, the technology described herein provides a novel expansion to the field of targeted protein degradation.