Rational Design and Synthesis of Novel Dimeric Diketoacid-Containing Inhibitors of HIV-1 Integrase:  Implication for Binding to Two Metal Ions on the Active Site of Integrase

2004 ◽  
Vol 47 (10) ◽  
pp. 2561-2573 ◽  
Author(s):  
Ya-Qiu Long ◽  
Xiao-Hua Jiang ◽  
Raveendra Dayam ◽  
Tino Sanchez ◽  
Robert Shoemaker ◽  
...  
Keyword(s):  
Metal Ions ◽  
Active Site ◽  
Rational Design ◽  
Design And Synthesis ◽  
Hiv 1

Rational design and synthesis of novel thiazolidin-4-ones as non-nucleoside HIV-1 reverse transcriptase inhibitors

2014 ◽  
Vol 22 (12) ◽  
pp. 3159-3170 ◽  
Author(s):  
Vanangamudi Murugesan ◽  
Nandini Makwana ◽  
Rahul Suryawanshi ◽  
Reshu Saxena ◽  
Rajkamal Tripathi ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Rational Design ◽  
Reverse Transcriptase Inhibitors ◽  
Design And Synthesis ◽  
Hiv 1

scholarly journals Structural and Binding Analysis of Pyrimidinol Carboxylic Acid andN-Hydroxy Quinazolinedione HIV-1 RNase H Inhibitors

2011 ◽  
Vol 55 (6) ◽  
pp. 2905-2915 ◽  
Author(s):  
Eric B. Lansdon ◽  
Qi Liu ◽  
Stephanie A. Leavitt ◽  
Mini Balakrishnan ◽  
Jason K. Perry ◽  
...  
Keyword(s):  
Carboxylic Acid ◽  
Metal Ions ◽  
Active Site ◽  
Water Environment ◽  
Divalent Metal ◽  
Rnase H ◽  
Accurate Assessment ◽  
Divalent Metal Ions ◽  
Substrate State ◽  
Hiv 1

ABSTRACTHIV-1 RNase H breaks down the intermediate RNA-DNA hybrids during reverse transcription, requiring two divalent metal ions for activity. Pyrimidinol carboxylic acid andN-hydroxy quinazolinedione inhibitors were designed to coordinate the two metal ions in the active site of RNase H. High-resolution (1.4 Å to 2.1 Å) crystal structures were determined with the isolated RNase H domain and reverse transcriptase (RT), which permit accurate assessment of the metal and water environment at the active site. The geometry of the metal coordination suggests that the inhibitors mimic a substrate state prior to phosphodiester catalysis. Surface plasmon resonance studies confirm metal-dependent binding to RNase H and demonstrate that the inhibitors do not bind at the polymerase active site of RT. Additional evaluation of the RNase H site reveals an open protein surface with few additional interactions to optimize active-site inhibitors.

scholarly journals Studies towards the Design and Synthesis of Novel 1,5-Diaryl-1H-imidazole-4-carboxylic Acids and 1,5-Diaryl-1H-imidazole-4-carbohydrazides as Host LEDGF/p75 and HIV-1 Integrase Interaction Inhibitors

Molecules ◽  
2021 ◽  
Vol 26 (20) ◽  
pp. 6203
Author(s):  
Thompho J. Rashamuse ◽  
Muhammad Q. Fish ◽  
E. Mabel Coyanis ◽  
Moira L. Bode
Keyword(s):  
Western Blot ◽  
Carboxylic Acids ◽  
Active Site ◽  
Binding Pocket ◽  
Strand Transfer ◽  
Inhibition Assay ◽  
Design And Synthesis ◽  
A Cell ◽  
Inhibitory Threshold ◽  
Hiv 1

Two targeted sets of novel 1,5-diaryl-1H-imidazole-4-carboxylic acids 10 and carbohydrazides 11 were designed and synthesized from their corresponding ester intermediates 17, which were prepared via cycloaddition of ethyl isocyanoacetate 16 and diarylimidoyl chlorides 15. Evaluation of these new target scaffolds in the AlphaScreenTM HIV-1 IN-LEDGF/p75 inhibition assay identified seventeen compounds exceeding the pre-defined 50% inhibitory threshold at 100 µM concentration. Further evaluation of these compounds in the HIV-1 IN strand transfer assay at 100 μM showed that none of the compounds (with the exception of 10a, 10l, and 11k, with marginal inhibitory percentages) were actively bound to the active site, indicating that they are selectively binding to the LEDGF/p75-binding pocket. In a cell-based HIV-1 antiviral assay, compounds 11a, 11b, 11g, and 11h exhibited moderate antiviral percentage inhibition of 33–45% with cytotoxicity (CC50) values of >200 µM, 158.4 µM, >200 µM, and 50.4 µM, respectively. The antiviral inhibitory activity displayed by 11h was attributed to its toxicity. Upon further validation of their ability to induce multimerization in a Western blot gel assay, compounds 11a, 11b, and 11h appeared to increase higher-order forms of IN.

scholarly journals Rational Design and Synthesis of Right-Handed d-Sulfono-γ-AApeptide Helical Foldamers as Potent Inhibitors of Protein–Protein Interactions

2020 ◽  
Vol 85 (16) ◽  
pp. 10552-10560
Author(s):  
Peng Sang ◽  
Yan Shi ◽  
Pirada Higbee ◽  
Minghui Wang ◽  
Sami Abdulkadir ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Rational Design ◽  
Protein Protein Interactions ◽  
Design And Synthesis
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