Tetrahydrofuran, Tetrahydropyran, Triazoles and Related Heterocyclic Derivatives as HIV Protease Inhibitors

Ghosh, Arun K.; Anderson, David D.

doi:10.4155/fmc.11.68

Cited by 53 publications

(33 citation statements)

References 75 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Experimental details of the syntheses of PIs GRL-0489A, GRL-0249A and GRl-044-10A have been described [17, 37, 39, 57]. Synthesis of PI UIC-94003 carried out using procedure described previously [58].…”

Section: Methodsmentioning

confidence: 99%

A fission yeast cell-based system for multidrug resistant HIV-1 proteases

Benkő

Dong

et al. 2017

Cell Biosci

View full text Add to dashboard Cite

BackgroundHIV-1 protease (PR) is an essential enzyme for viral production. Thus, PR inhibitors (PIs) are the most effective class of anti-HIV drugs. However, the main challenge to the successful use of PI drugs in patient treatment is the emergence of multidrug resistant PRs (mdrPRs). This study aimed to develop a fission yeast cell-based system for rapid testing of new PIs that combat mdrPRs.ResultsThree mdrPRs were isolated from HIV-infected patients that carried seven (M7PR), ten (M10PR) and eleven (M11PR) PR gene mutations, respectively. They were cloned and expressed in fission yeast under an inducible promoter to allow the measurement of PR-specific proteolysis and drug resistance. The results showed that all three mdrPRs maintained their abilities to proteolyze HIV viral substrates (MA↓CA and p6) and to confer drug resistance. Production of these proteins in the fission yeast caused cell growth inhibition, oxidative stress and altered mitochondrial morphologies that led to cell death. Five investigational PIs were used to test the utility of the established yeast system with an FDA-approved PI drug Darunavir (DRV) as control. All six compounds suppressed the wildtype PR (wtPR) and the M7PR-mediated activities. However, none of them were able to suppress the M10PR or the M11PR.ConclusionsThe three clinically isolated mdrPRs maintained their viral proteolytic activities and drug resistance in the fission yeast. Furthermore, those viral mdrPR activities were coupled with the induction of growth inhibition and cell death, which could be used to test the PI activities. Indeed, the five investigational PIs and DRV suppressed the wtPR in fission yeast as they did in mammalian cells. Significantly, two of the high level mdrPRs (M10PR and M11PR) were resistant to all of the existing PI drugs including DRV. This observation underscores the importance of continued searching for new PIs against mdrPRs.Electronic supplementary materialThe online version of this article (doi:10.1186/s13578-016-0131-5) contains supplementary material, which is available to authorized users.

show abstract

Section: Methodsmentioning

confidence: 99%

A fission yeast cell-based system for multidrug resistant HIV-1 proteases

Benkő

Dong

et al. 2017

Cell Biosci

View full text Add to dashboard Cite

show abstract

“…Such scaffolds offer many desirable properties that make them important in molecular design. Heterocycles itself may directly bind to the enzyme forming hydrogen bonds or hydrophobic interactions which results into increased potential [19]. It has been well established that the heterocyclic rings will play a major role in HIV-1 inhibitors due to their conformational restriction as well as their ability to fill hydrophobic pockets and provide functionality for hydrogen bonding interactions [19].…”

Section: Structure-based Design Approachmentioning

confidence: 99%

Inhibiting Activity of HIV-1: Protease, Reverse Transcriptase and Integrase All Together by Novel Compounds Using Computational Approaches

Kalathiya¹,

Padariya²

2014

IJBBB

View full text Add to dashboard Cite

Acquired immunodeficiency syndrome (AIDS), caused by human immunodeficiency virus type 1 (HIV-1) infection, is one of the most challenging diseases in recent decades. Nevertheless the shortcomings of chemical drugs such as toxicity, lack of curative effects, the search for more potent anti-HIV agents have been focused in our study. In current study, novel scaffold was designed to having a benzyl and imidazole in it which are very important functional groups to available HIV-1 inhibitors. Based on our novel scaffold, different compounds were designed by adding functions groups at R1 and R2 ends which taken from some FDA approved inhibitors (a reverse design approach). Designed ligands were tested individually with HIV-1 protease, reverse transcriptase and integrase enzymes. Flexible and rigid docking approaches were applied to all complexes and comparative analysis of results was done. Compound C0M5 containing functional groups pyridyl methyl piperazine with acetamide at R1 and indanol at R2 end, and compound C0M8 having cyclopentenopyridine with N-methylacetamide at R1 and octahydro-1H-isochromeneare at R2 end has shown potential bindings with HIV-1 enzymes. Outcome of proposed work suggests that, designed compound performed as the multifunctional ligands and has the tendency to interact with integrase, reverse transcriptase and integrase with efficient bindings and can be considered as potential inhibitors of HIV-1 enzymes for further testing.

show abstract

“…Ligand Design: It has been well established that the heterocyclic rings will play a major role in HIV-1 inhibitors due to their conformational restriction as well as their ability to fill hydrophobic pockets and provide functionality for hydrogen bonding interactions 13 . The Pyrimidine based molecule is the important class of compound.…”

Section: Materials and Methods: Preparation Of Receptor Enzymementioning

confidence: 99%

Untitled

2019

IJPSR

View full text Add to dashboard Cite

Tetrahydrofuran, Tetrahydropyran, Triazoles and Related Heterocyclic Derivatives as HIV Protease Inhibitors

Cited by 53 publications

References 75 publications

A fission yeast cell-based system for multidrug resistant HIV-1 proteases

A fission yeast cell-based system for multidrug resistant HIV-1 proteases

Inhibiting Activity of HIV-1: Protease, Reverse Transcriptase and Integrase All Together by Novel Compounds Using Computational Approaches

Untitled

Contact Info

Product

Resources

About