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Genome Biol ; 23(1): 236, 2022 Nov 08.
Article in English | MEDLINE | ID: covidwho-2108879


Effectively monitoring the spread of SARS-CoV-2 mutants is essential to efforts to counter the ongoing pandemic. Predicting lineage abundance from wastewater, however, is technically challenging. We show that by sequencing SARS-CoV-2 RNA in wastewater and applying algorithms initially used for transcriptome quantification, we can estimate lineage abundance in wastewater samples. We find high variability in signal among individual samples, but the overall trends match those observed from sequencing clinical samples. Thus, while clinical sequencing remains a more sensitive technique for population surveillance, wastewater sequencing can be used to monitor trends in mutant prevalence in situations where clinical sequencing is unavailable.

COVID-19 , SARS-CoV-2 , Humans , SARS-CoV-2/genetics , Waste Water , RNA, Viral/genetics , Transcriptome
Clin Infect Dis ; 2022 Jun 10.
Article in English | MEDLINE | ID: covidwho-1927317


We enrolled arriving international air travelers in SARS-CoV-2 genomic surveillance, using molecular testing of pooled nasal swabs, and sequencing positive samples for viral sublineage. Traveler-based genomic surveillance provided early warning variant detection; we reported the first U.S. Omicron BA.2 and first BA.3 in North America, weeks before next reported detection.

Proc Natl Acad Sci U S A ; 117(29): 17195-17203, 2020 07 21.
Article in English | MEDLINE | ID: covidwho-624792


The vast majority of intracellular protein targets are refractory toward small-molecule therapeutic engagement, and additional therapeutic modalities are needed to overcome this deficiency. Here, the identification and characterization of a natural product, WDB002, reveals a therapeutic modality that dramatically expands the currently accepted limits of druggability. WDB002, in complex with the FK506-binding protein (FKBP12), potently and selectively binds the human centrosomal protein 250 (CEP250), resulting in disruption of CEP250 function in cells. The recognition mode is unprecedented in that the targeted domain of CEP250 is a coiled coil and is topologically featureless, embodying both a structural motif and surface topology previously considered on the extreme limits of "undruggability" for an intracellular target. Structural studies reveal extensive protein-WDB002 and protein-protein contacts, with the latter being distinct from those seen in FKBP12 ternary complexes formed by FK506 and rapamycin. Outward-facing structural changes in a bound small molecule can thus reprogram FKBP12 to engage diverse, otherwise "undruggable" targets. The flat-targeting modality demonstrated here has the potential to expand the druggable target range of small-molecule therapeutics. As CEP250 was recently found to be an interaction partner with the Nsp13 protein of the SARS-CoV-2 virus that causes COVID-19 disease, it is possible that WDB002 or an analog may exert useful antiviral activity through its ability to form high-affinity ternary complexes containing CEP250 and FKBP12.

Actinobacteria/genetics , Antiviral Agents/pharmacology , Genome, Bacterial , Macrolides/pharmacology , Protein Interaction Domains and Motifs/drug effects , Small Molecule Libraries/pharmacology , Tacrolimus Binding Protein 1A/chemistry , Tacrolimus Binding Protein 1A/metabolism , Actinobacteria/metabolism , Amino Acid Sequence , Antiviral Agents/chemistry , Antiviral Agents/metabolism , Autoantigens/genetics , Autoantigens/metabolism , Calcineurin/genetics , Calcineurin/metabolism , Cell Cycle Proteins/genetics , Cell Cycle Proteins/metabolism , Evolution, Molecular , HEK293 Cells , Humans , Macrolides/chemistry , Macrolides/metabolism , Models, Molecular , Protein Conformation , Sequence Homology , Sirolimus/chemistry , Sirolimus/metabolism , Small Molecule Libraries/chemistry , Small Molecule Libraries/metabolism , TOR Serine-Threonine Kinases/genetics , TOR Serine-Threonine Kinases/metabolism