Structural basis for potent and broad inhibition of HIV-1 RT by thiophene[3,2-d]pyrimidine non-nucleoside inhibitors
- Yale University, United States
- Shandong University, China
- KU Leuven, Belgium
Abstract
Rapid generation of drug-resistant mutations in HIV-1 reverse transcriptase (RT), a prime target for anti-HIV therapy, poses a major impediment to effective anti-HIV treatment. Our previous efforts have led to the development of two novel non-nucleoside reverse transcriptase inhibitors (NNRTIs) with piperidine-substituted thiophene[3,2-d]pyrimidine scaffolds, compounds K-5a2 and 25a, which demonstrate highly potent anti-HIV-1 activities and improved resistance profiles compared with etravirine and rilpivirine, respectively. Here, we have determined the crystal structures of HIV-1 wild-type (WT) RT and seven RT variants bearing prevalent drug-resistant mutations in complex with K-5a2 or 25a at ~2 Å resolution. These high-resolution structures illustrate the molecular details of the extensive hydrophobic interactions and the network of main chain hydrogen bonds formed between the NNRTIs and the RT inhibitor binding pocket, and provide valuable insights into the favorable structural features that can be employed for designing NNRTIs that are broadly active against drug-resistant HIV-1 variants.
Data availability
Diffraction data and atomic coordinates have been deposited in the Protein Data Bank under the accession codes 6C0J, 6C0K, 6C0L, 6CGF, 6C0N, 6C0O, 6C0P, 6C0R, 6DUF, 6DUG, and 6DUH.
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Crystal structure of HIV-1 reverse transcriptase in complex with nonnucleoside inhibitor K-5a2Publicly available at the RCSB Protein Data Bank (accession no. 6C0J).
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Crystal structure of HIV-1 K103N mutant reverse transcriptase in complex with non-nucleoside inhibitor K-5a2Publicly available at the RCSB Protein Data Bank (accession no. 6C0K).
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Crystal structure of HIV-1 E138K mutant reverse transcriptase in complex with non-nucleoside inhibitor K-5a2Publicly available at the RCSB Protein Data Bank (accession no. 6C0L).
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Crystal structure of HIV-1 Y188L mutant reverse transcriptase in complex with non-nucleoside inhibitor K-5a2Publicly available at the RCSB Protein Data Bank (accession no. 6CGF).
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Crystal structure of HIV-1 reverse transcriptase in complex with non-nucleoside inhibitor 25aPublicly available at the RCSB Protein Data Bank (accession no. 6C0N).
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Crystal structure of HIV-1 K103N mutant reverse transcriptase in complex with non-nucleoside inhibitor 25aPublicly available at the RCSB Protein Data Bank (accession no. 6C0O).
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Crystal structure of HIV-1 E138K mutant reverse transcriptase in complex with non-nucleoside inhibitor 25aPublicly available at the RCSB Protein Data Bank (accession no. 6C0P).
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Crystal structure of HIV-1 K103N/Y181C mutant reverse transcriptase in complex with non-nucleoside inhibitor 25aPublicly available at the RCSB Protein Data Bank (accession no. 6C0R).
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Crystal structure of HIV-1 reverse transcriptase V106A/F227L mutant in complex with non-nucleoside inhibitor 25aPublicly available at the RCSB Protein Data Bank (accession no. 6DUF).
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Crystal structure of HIV-1 reverse transcriptase K101P mutant in complex with non-nucleoside inhibitor 25aPublicly available at the RCSB Protein Data Bank (accession no. 6DUG).
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Crystal structure of HIV-1 reverse transcriptase Y181I mutant in complex with non-nucleoside inhibitor 25aPublicly available at the RCSB Protein Data Bank (accession no. 6DUH).
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Crystal structure of HIV-1 reverse transcriptase (RT) in complex with Rilpivirine (TMC278, Edurant), a non-nucleoside rt-inhibiting drugPublicly available at the RCSB Protein Data Bank (accession no. 4G1Q).
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HIV-1 Reverse Transcriptase in Complex with TMC125Publicly available at the RCSB Protein Data Bank (accession no. 3MEC).
Article and author information
Author details
Funding
Howard Hughes Medical Institute (Investigator Program)
- Thomas A Steitz
National Institute of General Medical Sciences (GM022778)
- Thomas A Steitz
National Natural Science Foundation of China (81273354)
- Xinyong Liu
Key research and development project of Shandong Province (2017CXGC1401)
- Xinyong Liu
Major Project of Science and Technology of Shandong Province (2015ZDJS04001)
- Xinyong Liu
Young Scholars Program of Shandong University (2016WLJH32)
- Peng Zhan
Key Project of National Natural Science Foundation of China for International Cooperation (81420108027)
- Xinyong Liu
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2018, Yang et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Structural basis for potent and broad inhibition of HIV-1 RT by thiophene[3,2-d]pyrimidine non-nucleoside inhibitors
eLife 7:e36340.
https://doi.org/10.7554/eLife.36340
Further reading
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- Medicine
- Microbiology and Infectious Disease
Background:
Under which conditions antibiotic combination therapy decelerates rather than accelerates resistance evolution is not well understood. We examined the effect of combining antibiotics on within-patient resistance development across various bacterial pathogens and antibiotics.
Methods:
We searched CENTRAL, EMBASE, and PubMed for (quasi)-randomised controlled trials (RCTs) published from database inception to 24 November 2022. Trials comparing antibiotic treatments with different numbers of antibiotics were included. Patients were considered to have acquired resistance if, at the follow-up culture, a resistant bacterium (as defined by the study authors) was detected that had not been present in the baseline culture. We combined results using a random effects model and performed meta-regression and stratified analyses. The trials’ risk of bias was assessed with the Cochrane tool.
Results:
42 trials were eligible and 29, including 5054 patients, qualified for statistical analysis. In most trials, resistance development was not the primary outcome and studies lacked power. The combined odds ratio for the acquisition of resistance comparing the group with the higher number of antibiotics with the comparison group was 1.23 (95% CI 0.68–2.25), with substantial between-study heterogeneity (I2=77%). We identified tentative evidence for potential beneficial or detrimental effects of antibiotic combination therapy for specific pathogens or medical conditions.
Conclusions:
The evidence for combining a higher number of antibiotics compared to fewer from RCTs is scarce and overall compatible with both benefit or harm. Trials powered to detect differences in resistance development or well-designed observational studies are required to clarify the impact of combination therapy on resistance.
Funding:
Support from the Swiss National Science Foundation (grant 310030B_176401 (SB, BS, CW), grant 32FP30-174281 (ME), grant 324730_207957 (RDK)) and from the National Institute of Allergy and Infectious Diseases (NIAID, cooperative agreement AI069924 (ME)) is gratefully acknowledged.
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- Evolutionary Biology
- Microbiology and Infectious Disease
The global rise of antibiotic resistance calls for new drugs against bacterial pathogens. A common approach is to search for natural compounds deployed by microbes to inhibit competitors. Here, we show that the iron-chelating pyoverdines, siderophores produced by environmental Pseudomonas spp., have strong antibacterial properties by inducing iron starvation and growth arrest in pathogens. A screen of 320 natural Pseudomonas isolates used against 12 human pathogens uncovered several pyoverdines with particularly high antibacterial properties and distinct chemical characteristics. The most potent pyoverdine effectively reduced growth of the pathogens Acinetobacter baumannii, Klebsiella pneumoniae, and Staphylococcus aureus in a concentration- and iron-dependent manner. Pyoverdine increased survival of infected Galleria mellonella host larvae and showed low toxicity for the host, mammalian cell lines, and erythrocytes. Furthermore, experimental evolution of pathogens combined with whole-genome sequencing revealed limited resistance evolution compared to an antibiotic. Thus, pyoverdines from environmental strains have the potential to become a new class of sustainable antibacterials against specific human pathogens.
