Chemical Synthesis of an Enzyme Containing an Artificial Catalytic Apparatus

2020 ◽  
Vol 73 (4) ◽  
pp. 321
Author(s):  
Vladimir Torbeev ◽  
Stephen B. H. Kent

With the goal of investigating electronic aspects of the catalysis of peptide bond hydrolysis, an analogue of HIV-1 protease was designed in which a non-peptide hydroxy-isoquinolinone artificial catalytic apparatus replaced the conserved Asp25–Thr26–Gly27 sequence in each 99-residue polypeptide chain of the homodimeric enzyme molecule. The enzyme analogue was prepared by total chemical synthesis and had detectable catalytic activity on known HIV-1 protease peptide substrates. Compared with uncatalyzed hydrolysis, the analogue enzyme increased the rate of peptide bond hydrolysis by ∼108-fold. Extensions of this unique approach to the study of enzyme catalysis in HIV-1 protease are discussed.

2016 ◽  
Vol 14 (37) ◽  
pp. 8804-8814
Author(s):  
David J. Boerema ◽  
Valentina A. Tereshko ◽  
Junliang Zhang ◽  
Stephen B. H. Kent

Adenine covalently attached to the RNase A enzyme molecule decreased the rate of transphosphorylation and increased the rate of hydrolysis.


2020 ◽  
Vol 26 (8) ◽  
pp. 802-814 ◽  
Author(s):  
Nemanja Turkovic ◽  
Branka Ivkovic ◽  
Jelena Kotur-Stevuljevic ◽  
Milica Tasic ◽  
Bojan Marković ◽  
...  

Background: Since the beginning of the HIV/AIDS epidemic, 75 million people have been infected with the HIV and about 32 million people have died of AIDS. Investigation of the molecular mechanisms critical to the HIV replication cycle led to the identification of potential drug targets for AIDS therapy. One of the most important discoveries is HIV-1 protease, an enzyme that plays an essential role in the replication cycle of HIV. Objective: The aim of the present study is to synthesize and investigate anti-HIV-1 protease activity of some chalcone derivatives with the hope of discovering new lead structure devoid drug resistance. Methods: 20 structurally similar chalcone derivatives were synthesized and their physico-chemical characterization was performed. Binding of chalcones to HIV-1 protease was investigated by fluorimetric assay. Molecular docking studies were conducted to understand the interactions. Results: The obtained results revealed that all compounds showed anti-HIV-1 protease activity. Compound C1 showed the highest inhibitory activity with an IC50 value of 0.001 μM, which is comparable with commercial product Darunavir. Conclusion: It is difficult to provide general principles of inhibitor design. Structural properties of the compounds are not the only consideration; ease of chemical synthesis, low molecular weight, bioavailability, and stability are also of crucial importance. Compared to commercial products the main advantage of compound C1 is the ease of chemical synthesis and low molecular weight. Furthermore, compound C1 has a structure that is different to peptidomimetics, which could contribute to its stability and bioavailability.


1998 ◽  
Vol 63 (4) ◽  
pp. 541-548 ◽  
Author(s):  
Jaroslav Litera ◽  
Jan Weber ◽  
Ivana Křížová ◽  
Iva Pichová ◽  
Jan Konvalinka ◽  
...  

Twelve pseudotetrapeptides, Boc-NHCH(CH2Ph)CH(OH)CH2CH(CH2Ph) CO-Xaa-Phe-NH2 9-11, were prepared by [(benzotriazol-1-yl)oxy]tris(dimethylamino)phosphonium hexafluorophosphate-mediated couplings of diastereoisomeric O-silylated (2R or 2S,4R or 4S,5S)-2-benzyl-5-(tert-butoxycarbonyl)amino-4-hydroxy-6-phenylhexanoic acids 1 with dipeptides H-Xaa-Phe-NH2 (Xaa = Gln, Glu(OBzl) or Ile) 3-5, followed by O-deprotection. Pseudotetrapeptides 9-11 were tested for inhibition of aspartic proteinases secreted by Candida albicans and C. tropicalis. The level of inhibition of both yeast proteinases was very low, contrasting with the nanomolar IC50 values obtained for inhibition of HIV-1 proteinase.


2007 ◽  
Vol 13 (1-2) ◽  
pp. 221-227 ◽  
Author(s):  
Silvia Frutos ◽  
Judit Tulla-Puche ◽  
Fernando Albericio ◽  
Ernest Giralt

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