April 6, 2021
New inhibitors may offer novel approach to treating deadly tuberculosis
WEST LAFAYETTE, Ind. – Purdue University innovators have developed highly potent and selective compounds for use in the treatment of tuberculosis, which is one of the top 10 causes of death worldwide.
The Purdue researchers developed a series of small molecule inhibitors to target one of the proteins critical for the survival of TB in infected macrophages. Protein tyrosine phosphates B (mPTPB) is a virulence factor of TB to subvert the host immune responses.
The Purdue research is published in the Journal of Medicinal Chemistry.
“The death toll from TB is particularly high because of drug-resistant strains,” said Zhong-Yin Zhang, distinguished professor and head of Purdue’s Department of Medicinal Chemistry and Molecular Pharmacology and director of Purdue Institute for Drug Discovery. “These inhibitors are part of a promising new approach to developing TB therapeutic agents with novel targets and mechanisms of action to help save more lives.”
Current treatments for TB are mostly antibiotic-based solutions. A major problem is that a large number of patients fail to take the entire antibiotic regime, which can lead to drug-resistant strains.
“We developed a platform to target mPTPB for novel anti-TB agents that builds on technologies we pioneered to modulate abnormal protein tyrosine phosphatase activity for the treatment of diseases such as cancer, diabetes and autoimmune disorders,” Zhang said.
Zhang said these inhibitors’ properties also make them promising drug candidates. They possess lighter molecular weights, excellent metabolic stability and bioavailability to provide a starting point for further therapeutic development for use as TB treatments.
The innovators and OTC are looking for partners to continue developing their technology. For more information on licensing and other opportunities, contact Joseph Kasper of OTC at firstname.lastname@example.org and mention track code 2020-ZHAN-68995.
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Highly Potent and Selective N-Aryl Oxamic Acid-Based Inhibitors for Mycobacterium tuberculosis Protein Tyrosine Phosphatase B
Kasi Viswanatharaju Ruddraraju, Devesh Aggarwal, Congwei Niu, Erica Anne Baker, Ruo-yu Zhang, Li Wu and Zhong-Yin Zhang
Tuberculosis is an infectious disease caused by the bacterium Mycobacterium tuberculosis (Mtb). Mtb protein tyrosine phosphatase B (mPTPB) is a virulence factor required for Mtb survival in host macrophages. Consequently, mPTPB represents an exciting target for tuberculosis treatment. Here, we identified N-phenyl oxamic acid as a highly potent and selective monoacid-based phosphotyrosine mimetic for mPTPB inhibition. SAR studies on the initial hit, compound 4 (IC50 = 257 nM), resulted in several highly potent inhibitors with IC50 values lower than 20 nM for mPTPB. Among them, compound 4t showed a Ki of 2.7 nM for mPTPB with over 4500-fold preference over 25 mammalian PTPs. Kinetic, molecular docking, and site-directed mutagenesis analyses confirmed these compounds as active site-directed reversible inhibitors of mPTPB. These inhibitors can reverse the altered host cell immune responses induced by the bacterial phosphatase. Furthermore, the inhibitors possess molecular weights <400 Da, log D7.4 < 2.5, topological polar surface area < 75, ligand efficiency > 0.43, and good aqueous solubility and metabolic stability, thus offering excellent starting points for further therapeutic development.