Mycobacterium tuberculosis (Mtb), the infectious agent of tuberculosis (TB), causes over 1.5 million deaths globally every year. Host-directed therapies (HDT) for TB are desirable for their potential to shorten treatment and reduce the development of antibiotic resistance. Previously, we described a modular biomimetic strategy to identify SMIP-30, targeting PPM1A (IC₅₀ = 1.19 μM), a metal-dependent phosphatase exploited by Mtb to survive intracellularly. SMIP-30 restricted the survival of Mtb in macrophages and lungs of infected mice. Herein, we redesigned SMIP-30 to create SMIP-031, which is a more potent inhibitor for PPM1A (IC₅₀ = 180 nM). SMIP-031 efficiently increased the level of phosphorylation of S403-p62 and the expression of LC3B-II to activate autophagy, resulting in the dose-dependent clearance of Mtb in infected macrophages. SMIP-031 possesses a good pharmacokinetic profile and oral bioavailability (F = 74%). In vivo, SMIP-031 is well tolerated up to 50 mg/kg and significantly reduces the bacteria burden in the spleens of infected mice.

01 Dec 2022·Acta Pharmaceutica Sinica B

SMIP-30, a potent and selective PPM1A inhibitor with potential to treat tuberculosis

Article

Author: Xu, Shujing ; Liu, Xinyong ; Zhan, Peng

Recently, a collaborative research led by Weibo Yang and Jim Sun published in Cell Chem. Biol. identified a potent and selective small mol. inhibitor (SMIP-30) for human protein phosphatase Mg2+/Mn 2+-dependent 1A (PPM1A).They applied this chem. probe to determine the autophagy receptor p62 as a new substrate of PPM1A, and proved that SMIP-30 could enhance the selective autophagy of macrophages to limit the survival of intracellular Mycobacterium tuberculosis (Mtb).These findings should promote new therapeutic modalities to overcome tuberculosis (TB).The PPM1A inhibitor SMIP-30 enhances the phosphorylation of p62, making it more accessible to label Mtb exposed to the cytoplasm and target it to autophagosomes.The inhibition of PPM1A by SMIP-30 directly acts on the early stage of autophagy, providing a unique way to induce autophagy in Mtb-infected cells and expanding the available library of druggable targets.Addnl., to reduce exposure to non-target cells and undesired side effects, developing immunomodulatory nanoparticle-based therapies for Mtb infection will achieve more targeted drug delivery, reduce harmful side effects, and increase drug concentrations in target cells.

01 Sep 2022·STAR Protocols

An in vivo biosafety-level-2-compatible model of Mycobacterium tuberculosis infection for drug susceptibility testing

Article

Author: Berton, Stefania ; Liang, Yi Chu ; Sun, Jim ; Reeks, Courtney

Available mouse models for tuberculosis drug susceptibility testing requires using virulent biosafety-level-3 (BSL-3) Mycobacterium tuberculosis (Mtb) strains, or attenuated BSL-2 strains that lack virulence genes. Here, we present a BSL-2-compatible mouse model for tuberculosis drug susceptibility testing using the auxotrophic Mtb mc²6206 strain, which retains all virulence genes. Using rifampicin and a new autophagy-boosting compound, SMIP-30, we provide a step-by-step guide for the infection, drug administration, and evaluation of Mtb burden and cytokine profiles. This protocol is easily adaptable for testing of other antibiotics and host-directed compounds. For complete details on the use and execution of this protocol, please refer to Berton et al. (2022).

100 Deals associated with SMIP-30

R&D Status

10 top R&D records.

to view more data

Indication	Highest Phase	Country/Location	Organization	Date
Tuberculosis	Preclinical	Canada	University of Ottawa	01 Jul 2022

Clinical Result

Indication

Phase

Evaluation

View All Results

Translational Medicine

Boost your research with our translational medicine data.

view full example data

Deal

Boost your decision using our deal data.

view full example data

Core Patent

Boost your research with our Core Patent data.

view full example data

Clinical Trial

Identify the latest clinical trials across global registries.

view full example data

Approval

Accelerate your research with the latest regulatory approval information.

view full example data

Regulation

Understand key drug designations in just a few clicks with Synapse.

view full example data

AI Agents Built for Biopharma Breakthroughs

Accelerate discovery. Empower decisions. Transform outcomes.

Get started for free today!

Accelerate Strategic R&D decision making with Synapse, PatSnap’s AI-powered Connected Innovation Intelligence Platform Built for Life Sciences Professionals.

Start your data trial now!

Synapse data is also accessible to external entities via APIs or data packages. Empower better decisions with the latest in pharmaceutical intelligence.

Bio

Bio Sequences Search & Analysis

Chemical

Chemical Structures Search & Analysis


No Data

SMIP-30

Overview

Basic Info

Structure/Sequence

Related

R&D Status

Clinical Result

Translational Medicine

Deal

Core Patent

Clinical Trial

Approval

Regulation