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THE TARGETS

Serine hydrolases are validated, but largely under explored drug targets

  • Family includes lipases, amidases, esterases, thioesterases, proteases and peptidases, which share a base-activated serine nucleophile that cleaves an amide or ester bond
  • Serine hydrolases play a key role in regulating CNS signaling, digestion, metabolism, inflammation, blood clotting, life cycle of viruses and pathogens
  • Abide technology selectively and near-universally targets this enzyme class in their native configuration

Activity Based Protein Profiling (ABPP) Technology for Inhibitor Discovery

Active serine hydrolases are rapidly and covalently labeled with fluorophosphonate-based activity probes. These probes can be conjugated to fluorophores for imaging or to biotin for affinity purification and mass spectrometry.

Inhibitor-treated proteomes from cells or tissues are labeled with activity-based probes. Probe-treated proteomes can then be visualized by SDS-PAGE and in-gel fluorescence scanning for rapid selectivity profiling. Alternatively, affinity purification of probe-labeled enzymes, combined with SILAC-based high-resolution mass-spectrometry, enables the simultaneous measurement of inhibitor sensitivity for all serine hydrolases with unprecedented sensitivity and accuracy.

THE PRODUCT ENGINE

The human serine hydrolase family has over 200 members, including lipases, amidases, esterases, thioesterases, proteases and peptidases that participate in nearly all aspects of human physiology.

serine hydrolases

The genomes of pathogenic prokaryotes are also replete with serine hydrolases that include validated therapeutic targets (for example, penicillin-binding proteins) as well as numerous enzymes with untapped therapeutic potential.

Species/strain Disease Gram Genome size
(# of genes)
Serine hydrolases Serine hydrolases
(% of proteome)
Mycobacterium tuberculosis Tuberculosis Positive 3,990 154 3.9%
Bacillus anthracis Anthrax Positive 6,614 119 1.8%
Listeria monocytogenes Listeriosis Positive 2,818 41 1.5%
Methicillin-resistant Staphylococcus aureus (MRSA) Necrotizing
pneumonia
Positive 2,640 33 1.3%
Clostridium difficile Antibiotic-associated diarrhea Positive 3,784 36 1.0%
Burkholderia cepacia Pneumonia Negative 6,993 143 2.0%
Yersinia Pestis Bubonic plague Negative 5,739 54 0.9%
Vibrio Cholerae Cholera Negative 3,784 35 0.9%

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