Second generation HIV protease inhibitors against resistant virus

Lu, Zhijian

doi:10.1517/17460441.3.7.775

Cited by 10 publications

(3 citation statements)

References 64 publications

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“…Saquinavir, indinavir and nelfinavir are the first generation HIV protease inhibitors. Emerging of HIV resistance to these antiretroviral agents have become a problem in the treatment of acquired immunodeficiency syndrome (AIDS) patients (22). Therefore, it would be beneficial to explore other potentials of these agents and repurpose them for the treatment of other diseases.…”

Section: Resultsmentioning

confidence: 99%

Drug Repurposing of Clinically Approved Drugs to Target Epithelial-mesenchymal Transition Using Molecular Docking Approach

Chun Hao,

Chau Ling,

Harith

et al. 2023

MJMHS

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Introduction: Epithelial-mesenchymal transition (EMT) is a process of epithelial transformation into mesenchymal cells. It is also a process that contributes to the progression of fibrosis and cancer metastasis. Transforming growth factor-beta (TGF-β), as a potent inducer of EMT, has therefore became a potential therapeutic target. However, clinical developments of TGF-β inhibitors have been un-successful due to safety risks. Hence, drug repurposing of existing safe-to-use drugs could over-come this issue. Methods: In this study, the TGF-β receptor type 1 (ALK5) was selected as the target protein. Molecular docking was performed using known ALK5 inhibitors as positive controls. Clinical drugs with similar binding affinity and amino acid interaction were selected for in vitro experimental validation. Results: ALK5 inhibitor demonstrated binding affinities ranging from -11.2 to -9.5 kcal/mol. Analysis of amino acid interaction revealed that Val219, Ala230, Lys232, and Leu340 amino acid residues are crucial for binding. Subsequent screening of clinically approved drugs against ALK5 showed top five potential drugs (ergotamine, telmisartan, saquinavir, indinavir, and nelfinavir). The selected drugs were tested in TGF-β1-induced normal human bronchial epithelial cell line, BEAS-2B. Western blot analysis showed that the drugs did not exhibit inhibitory effects on the downregulation of epithelial proteins (E-cadherin) and upregulation of mesenchymal proteins (vimentin and α-smooth muscle actin). Conclusion: Based on these experimental outcome, it is postulated that the results from molecular docking were false positives. The tested drugs in this study could serve as negative controls in future screening against ALK5 protein.

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Section: Resultsmentioning

confidence: 99%

Drug Repurposing of Clinically Approved Drugs to Target Epithelial-mesenchymal Transition Using Molecular Docking Approach

Chun Hao,

Chau Ling,

Harith

et al. 2023

MJMHS

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“…In our studies, we tested HIV protease inhibitor drugs over a range of concentrations from 4 μM to 20 μM, which is similar to the therapeutic concentrations of the drugs 36 . Our biochemical findings are therefore consistent with the ability of similar concentrations of HIV-PIs to inhibit prelamin A processing in cultured cells as shown here and reported previously 16,17 .…”

Section: Discussionmentioning

confidence: 99%

Mass spectrometry captures off-target drug binding and provides mechanistic insights into the human metalloprotease ZMPSTE24

et al. 2016

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Off-target binding of hydrophobic drugs can lead to unwanted side effects, either through specific or nonspecific binding to unintended membrane protein targets; however, distinguishing the binding of drugs to membrane proteins from that of detergents, lipids and cofactors is challenging. Here we use high-resolution mass spectrometry to study the effects of HIV protease inhibitors on the human zinc metalloprotease ZMPSTE24. This intramembrane protease plays a major role in converting prelamin A to mature lamin A. We monitored proteolysis of farnesylated prelamin A peptide by ZMPSTE24 and unexpectedly found retention of the C-terminal peptide product with the enzyme. We also resolved binding of zinc, lipids, and HIV protease inhibitors and showed that drug binding blocked prelamin A peptide cleavage and conferred stability to ZMPSTE24. Our results not only have relevance for the progeria-like side effects of certain HIV protease inhibitor drugs but also highlight new approaches for documenting off-target drug binding.

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“…Second-generation protease inhibitors have extremely high binding affinity to viral protein [ 48 ]. Resistance to them typically requires more mutations than resistance to first-generation protease inhibitors and other antiretroviral drugs [ 49 , 50 ]. For example, mutation K103N on reverse transcriptase is sufficient to confer HIV-1 nevirapine (NVP) resistance [ 51 ], while more than 4 de novo mutations are needed for protease inhibitor Darunavir (DRV) resistance [ 52 ].…”

Section: Introductionmentioning

confidence: 99%

Predominance of positive epistasis among drug resistance-associated mutations in HIV-1 protease

et al. 2020

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Drug-resistant mutations often have deleterious impacts on replication fitness, posing a fitness cost that can only be overcome by compensatory mutations. However, the role of fitness cost in the evolution of drug resistance has often been overlooked in clinical studies or in vitro selection experiments, as these observations only capture the outcome of drug selection. In this study, we systematically profile the fitness landscape of resistance-associated sites in HIV-1 protease using deep mutational scanning. We construct a mutant library covering combinations of mutations at 11 sites in HIV-1 protease, all of which are associated with resistance to protease inhibitors in clinic. Using deep sequencing, we quantify the fitness of thousands of HIV-1 protease mutants after multiple cycles of replication in human T cells. Although the majority of resistance-associated mutations have deleterious effects on viral replication, we find that epistasis among resistance-associated mutations is predominantly positive. Furthermore, our fitness data are consistent with genetic interactions inferred directly from HIV sequence data of patients. Fitness valleys formed by strong positive epistasis reduce the likelihood of reversal of drug resistance mutations. Overall, our results support the view that strong compensatory effects are involved in the emergence of clinically observed resistance mutations and provide insights to understanding fitness barriers in the evolution and reversion of drug resistance.

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Second generation HIV protease inhibitors against resistant virus

Cited by 10 publications

References 64 publications

Drug Repurposing of Clinically Approved Drugs to Target Epithelial-mesenchymal Transition Using Molecular Docking Approach

Drug Repurposing of Clinically Approved Drugs to Target Epithelial-mesenchymal Transition Using Molecular Docking Approach

Mass spectrometry captures off-target drug binding and provides mechanistic insights into the human metalloprotease ZMPSTE24

Predominance of positive epistasis among drug resistance-associated mutations in HIV-1 protease

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