Post-translational import of protein into the endoplasmic reticulum of a trypanosome: an in vitro system for discovery of anti-trypanosomal chemical entities

Q3 · BIOLOGY

Article

Author: Duffy, Josh ; Davis, Richard C. ; Mensa-Wilmot, Kojo ; Patham, Bhargavi ; Wipf, Peter ; Lane, Ariel ; Brodsky, Jeffrey L. ; Fewell, Sheara W.

HAT (human African trypanosomiasis), caused by the protozoan parasite Trypanosoma brucei, is an emerging disease for which new drugs are needed. Expression of plasma membrane proteins [e.g. VSG (variant surface glycoprotein)] is crucial for the establishment and maintenance of an infection by T. brucei. Transport of a majority of proteins to the plasma membrane involves their translocation into the ER (endoplasmic reticulum). Thus inhibition of protein import into the ER of T. brucei would be a logical target for discovery of lead compounds against trypanosomes. We have developed a TbRM (T. brucei microsome) system that imports VSG_117 post-translationally. Using this system, MAL3-101, equisetin and CJ-21,058 were discovered to be small molecule inhibitors of VSG_117 translocation into the ER. These agents also killed bloodstream T. brucei in vitro; the concentrations at which 50% of parasites were killed (IC50) were 1.5 μM (MAL3-101), 3.3 μM (equisetin) and 7 μM (CJ-21,058). Thus VSG_117 import into TbRMs is a rapid and novel assay to identify ‘new chemical entities’ (e.g. MAL3-101, equisetin and CJ-21,058) for anti-trypanosome drug development.

01 Jan 2002·The Journal of AntibioticsQ4 · MEDICINE

CJ-21,058, a New SecA Inhibitor Isolated from a Fungus.

Q4 · MEDICINE

Article

Author: Yoshinao Kato ; Shinichi Sakemi ; Fadia Dib-Hajj ; Sae Inagaki ; Joyce Sutcliffe ; Chang-Hong Pang ; Hiroyuki Nishida ; Yasuhiro Kojima ; Toshiyuki Saito ; Yutaka Sugie ; John P. Mueller

A new equisetin derivative, CJ-21,058 (I) was isolated from the fermentation broth of an unidentified fungus CL47745. It shows antibacterial activity against Gram-positive multi-drug resistant bacteria by inhibiting ATP-dependent translocation of precursor proteins across a bacterial cell membrane.

Molecular Diversity

In silico screening of natural compounds as potential inhibitors against SecA protein of Acinetobacter baumannii

Article

Author: Swain, Aishwarya ; Pan, Archana ; Senapati, Smruti Sikha

SecA protein is a vital protein in bacterial protein transport systems and has been reported as a promising drug target in various bacteria, including the multidrug-resistant Acinetobacter baumannii for which development of novel drugs are urgently needed. To this end, the present study aims to screen natural compounds as potential inhibitors against SecA protein of this pathogen. Initially, structural modeling of SecA protein was performed to generate multiple models, which were assessed using various criteria. The most reliable model, Rank3 from AlphaFold2, was selected for molecular dynamics (MD) simulation study to obtain an energy-minimized structure. Virtual screening of this energy-minimized structure against the natural compound databases (LOTUS and CMNPD) identified five natural compounds, namely TCC, TMX, DDA, PF, and DOP with docking scores of - 9.801 kcal/mol, - 9.565 kcal/mol, - 9.092 kcal/mol, - 8.862 kcal/mol, and - 8.758 kcal/mol, respectively, which were significantly better than those of known SecA inhibitors CJ-21058 (- 3.92 kcal/mol), Pannomycin (- 3.234 kcal/mol), and Rose Bengal (- 2.608 kcal/mol). MD simulation studies confirmed the stability of protein-ligand complexes for all five compounds. Although DOP demonstrated the strongest binding energy (ΔG = - 46.93 ± 6.11 kcal/mol), it was excluded as it could cause respiratory toxicity and eye irritation. TMX, on the other hand, showed significant binding energy (ΔG = - 38.23 ± 2.97 kcal/mol), complex stability, good bioavailability, and an acceptable safety profile, indicating it as a potential inhibitor against SecA protein. Thus, our study uncovers a natural compound TMX as a potential inhibitor against a specific target protein. This can be further explored for experimental validation to develop novel drugs against the infectious diseases caused by A. baumannii/other related clinically important pathogens.

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Indication	Highest Phase	Country/Location	Organization	Date
Bacterial Infections	Discovery	United States	Pfizer Pharmaceuticals, Inc.	-

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