Inhibition of HIV-1 immune modulation by small molecules targeting viral Nef-host CD80 interface
Sharma, A. U.; Sharma, S.; Arumugam, G.; Nair, A. P.; Ambala, S.; Munagala, G.; Yempalla, K. R.; Munjal, A.; Rajkumar, S.; Kamariah, N.; Ramanathan, S.; Saiyed, T.; Venkitaraman, A. R.; Singh, P. P.; Vishwakarma, R.; Mayor, S.; Karumbati, A. S.
Show abstract
HIV-1 causes diverse immunomodulatory responses in the host, including the down-regulation of co-stimulatory proteins CD80/86, mediated by HIV-1 protein Nef, blunting T-cell activation. Using a screening cascade of biochemical and cell-based assays, we identified potent small molecules representing three chemical scaffolds namely amino pyrimidine, phenoxy acetamide and bi-aryl heteroaryl carbamate which target the protein-protein interaction interface of CD80/86 and Nef with sub-micromolar potency. These molecules restore CD80/86 surface levels in HIV-1-Nef infected antigen presenting cells and T-cell activation. Nef-CD80 interface and small molecule binding sites were mapped by using computational docking and structural studies, followed by validation by mutational analysis. This analysis resulted in the identification of two key residues, K99 and R111, which were associated with down-modulation of CD80 surface levels by Nef and important for small molecule binding. Targeting these interacting residues disabled Nef-mediated down-modulation of CD80 surface levels, consequently restoring T-cell activation. Thus, we validate a new target, the Nef-CD80/86 protein-protein interaction interface, with a potential to develop new inhibitors to counteract the immunomodulatory consequences of HIV-1.
Matching journals
The top 13 journals account for 50% of the predicted probability mass.
Similar papers in this journal
Similar papers in this journal
- Designing BH3-mimetic Peptide Inhibitors for the Viral Bcl-2 Homologs A179L and BHRF1: Importance of long-range electrostatic interactions 94%
- Chemical targeting of the ATXN1 aa99-163 interaction site suppresses polyQ-expanded protein dimerization 93%
- Chalcogen derivatives for the treatment of African trypanosomiasis: biological evaluation of thio and seleno- semicarbazones and their azole derivatives 93%
Similar papers in this journal
- Boceprevir, calpain inhibitors II and XII, and GC-376 have broad-spectrum antiviral activity against coronaviruses in cell culture 95%
- Drug repurposing screening identified tropifexor as a SARS-CoV-2 papain-like protease inhibitor 94%
- Identification and characterization of a small-molecule inhibitor of the Pseudomonas aeruginosa SOS response 93%
Similar papers in this journal
- Discovery of First-in-Class PROTAC Degraders of SARS-CoV-2 Main Protease 94%
- Discovery of CD28-Targeted Small Molecule Inhibitors of T Cell Co-stimulation Using Affinity Selection-Mass Spectrometry (AS-MS) and Ex Vivo Validation 94%
- Systematic development of peptide inhibitors targeting the CXCL12/HMGB1 interaction 94%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.