The goal of this proposal is to run a pilot study by screening 400 of the most promising antimalarial compounds against all serine hydrolases
, cysteine proteases, and ATPases found in infected red blood cells.
ABX-1431, which was discovered with Abide's proprietary technology platform targeting serine hydrolases
, has completed dosing in a first-in-human study assessing the safety, tolerability, pharmacodynamics, and pharmacokinetics of the molecule in single-ascending and multiple-ascending doses in healthy volunteers.
Acetyl cholinesterase (AChE) and butyryl cholinesterase (BChE) comprise a family of enzymes which include serine hydrolases
The product was discovered using the company's proprietary technology platform, which finds new small molecule drug candidates that target serine hydrolases
, a large class of enzymes with important regulatory roles in human physiology and disease.
The researchers have used a set of compounds, recently synthesized by Cravatt's laboratory, that tend to inhibit serine hydrolases
Metabolism of profenofos enantiomers yields a mixture of toxicants that includes direct-acting and cytochrome P450 (CYP450)-activated inhibitors of acetylcholinesterase (AChE) and other serine hydrolases
(Glickman et al.
Specific examples will focus on serine hydrolases
and kinases with applications to drug discovery and development.
The contract centres around Abide's technologies to selectively aim serine hydrolases
, "one of the largest enzyme families involved in regulating human physiology.
There are more than 200 serine hydrolases
in human cells, but for most we've lacked chemical inhibitors of their activity," said team leader Benjamin F.
Therefore, the molecular events that define esterase OP inhibition (including reactivation and aging; Figure 2) are likely to be similar to serine hydrolases
, serine proteases, and other related proteins.
Inhibition of the CESs by organophosphate xenobiotics (Table 4), such as carbophenothion, parathion, phosdrin, and TPP, was expected, because such compounds are common mechanistic suicide inhibitors of serine hydrolases
after activation to the oxon form (Casida and Quistad 2005).
They screened a group of enzymes known as serine hydrolases
by measuring the activity levels of these enzymes in normal prostate epithelial cells and in three standard prostate cancer cell lines.