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Structure Based Screening for Inhibitory Therapeutics of Ctla-4 Unveiled New Insights About Biology of Acth Publisher



Ramezani A1 ; Zakeri A2 ; Mardsoltani M3 ; Mohammadian A1 ; Hashemi ZS4 ; Mohammadpour H5 ; Jahangiri A6 ; Khalili S1, 2 ; Rasaee MJ1
Authors
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Authors Affiliations
  1. 1. Department of Medical Biotechnology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
  2. 2. Department of Biology Sciences, Shahid Rajaee Teacher Training University, Tehran, Iran
  3. 3. Department of Clinical Biochemistry, Faculty of Medical Sciences, Dezful University of Medical Sciences, Dezful, Iran
  4. 4. Department of Medical Biotechnology, School of Advanced Medical Technologies, Tehran University of Medical Science, Tehran, Iran
  5. 5. Department of Immunology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, 14263, NY, United States
  6. 6. Applied Microbiology Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran

Source: International Journal of Peptide Research and Therapeutics Published:2020


Abstract

Although the biology of adrenocorticotropic hormone (ACTH) protein has already been scrutinized, some functional aspects of its biology are yet to be elucidated in the context of immunological disorders. In this regard, virtual screening of a compound library was performed against the structure of Cytotoxic T-Lymphocyte Associated Protein-4 (CTLA-4) (assessed both spatially and energetically) to discover novel biological functions for ACTH. The results of virtual screening and the MD simulation demonstrated that DB01284 has high binding energy along with proper interaction orientation against CTLA-4 (FG loop) by a clamp like structure. The employed methodology was checked using confirmatory control analyses. Intriguingly, DB01284 belongs to Tetracosactide (already prescribed protein drug for clinical conditions) which is the N-terminal region of ACTH. This is the first study to reveal that ACTH protein binds to the same amino acids of CTLA-4 (FG-loop) as B7 and anti-CTLA-4 antibody binds. In light of this finding, the molecular mechanism of ACTH function in patients suffering from Cushing’s Syndrom and the immunological bases for ACTH therapy of multiple sclerosis (MS) patients could be further delineated. Moreover, this finding suggests that ACTH could also act to block CTLA-4 in the context of anticancer immune check point blockade. © 2019, Springer Nature B.V.
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