Methods and compounds are disclosed for irreversibly inhibiting a DNA polymerase, including DNA polymerase (pol ). Also disclosed are methods for inducing a synthetic lethality in a breast cancer type 1 (BRCA1)-deficient cancer cell, the method comprising inhibiting DNA polymerase by administering a presently disclosed pol inhibitor.

The present application discloses methods and apparatuses for single molecule drug screening, discovery and validation. These methods and apparatuses allow a user to detect rapidly, using observation of single molecules, whether and how a drug candidate interferes with a target enzyme involved in a particular disease pathway. The methods and apparatuses described herein utilize single molecule manipulation and detection technologies (e.g., optical or magnetic tweezers) to directly detect whether the characteristic dynamics, or mechanical signature, of the target enzyme-substrate interaction are substantially altered or modulated by a drug candidate. Furthermore, the methods and apparatuses are useful for analyzing the modulation of the mechanical signature in order to identify potential interference mechanisms of a drug candidate. In one aspect of the invention, the methods and apparatuses disclosed herein relate to monitoring the real-time dynamic mechanical signatures of individual polymerase molecules (e.g. DNA polymerases, RNA polymerases, and reverse transcriptases) along a polynucleotide substrate in the presence of drug candidates that either inhibit or otherwise modulate the polymerization process. Identification and analysis of such drug candidates is critical for anti-viral, anti-cancer, and antibiotic drug development.

The disclosure relates to compounds that are, e.g., PAP Associated Domain Containing 5 (PAPD5) inhibitors and methods of use thereof.

The present invention relates to influenza A virus variants, particularly variants that are resistant to a polymerase inhibitors. Also provided are methods and compositions related to the influenza A virus variants. Further provided are methods of isolating, identifying, and characterizing multiple viral variants from a patient.

The present invention relates to influenza A virus variants, particularly variants that are resistant to a polymerase inhibitors. Also provided are methods and compositions related to the influenza A virus variants. Further provided are methods of isolating, identifying, and characterizing multiple viral variants from a patient.

A method for performing a diagnostic assay for the detection of the presence or amount of a microorganism within a sample matrix containing active DNA polymerase, is disclosed. The method utilizes the measurement of DNA polymerase extension activity, wherein the assay comprises the steps of incubating DNA polymerase in the sample matrix with a selected suitable substrate, and performing PCR cycling and detection via the use of a selected suitable nucleic acid probe, thereby to detect endogenous DNA polymerase extension activity in the sample matrix as an indication of the presence or amount of said microorganism.

The present disclosure relates to novel NMNAT2 activators, semicarbazones and thiosemicarbazones, to processes for preparing them, to pharmaceutical preparations comprising them, to the method by administering the novel semicarbazones and thiosemicarbazones for the treatment and/or prevention of diseases and to the use thereof for the production of a medicament for the treatment and/or prevention of diseases, especially neurodegenerative and age-associated diseases or conditions associated with NAD loss. The present disclosure also provides a method for high throughput screening of NMNAT2 activators.

The invention provides a method of identifying a microorganism that expresses a nucleic acid-modifying enzyme, in sample, the method comprising: (a) contacting a nucleic acid substrate targeted by the nucleic acid-modifying enzyme with the sample; (b) adding a further nucleic acid molecule to the sample which nucleic acid molecule is ligated to the nucleic acid substrate in the presence of the nucleic acid-modifying enzyme to form a ligation product which comprises a linear single strand of nucleic acid that is capable of being detected; and (c) detecting the presence of the ligation product.

A gene sequencing method includes: hybridizing a sequencing primer and a molecule to be detected to form a template strand and a primer strand; linking a first nucleotide analog to the primer strand, wherein the first nucleotide analog has a blocking group; performing base pairing on a second nucleotide analog and the nucleic acid molecule to be detected, the second nucleotide analog forming a complex with the nucleic acid molecule to be detected and the first nucleotide analog under the action of metal ions and a polymerase, wherein the second nucleotide analog has a marker; detecting the marker, and identifying a base; and removing the blocking group and the second nucleotide analog, and performing a next cycle of sequencing. The gene sequencing method can completely remove blocking groups and markers without leaving synthetic scars, so that the sequencing length can be increased and the sequencing cost can be reduced.

Methods of screening for anti-pseudomonal compositions are disclosed that utilize a genetically engineered P. aeruginosa strain that is recA deficient and comprises a transcriptional reporter joined to at least a portion of a promoter for at least one gene of a pyocin gene cluster. The methods identify agents that stimulate pyocin expression in a RecA-independent manner. Also disclosed are agents identified by said methods, along with methods of producing and using same.