Structural basis for potent and broad inhibition of HIV-1 RT by thiophene[3,2-d]pyrimidine non-nucleoside inhibitors

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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.

The following data sets were generated

(2018) Crystal structure of HIV-1 reverse transcriptase in complex with nonnucleoside inhibitor K-5a2
Publicly available at the RCSB Protein Data Bank (accession no. 6C0J).

http://www.rcsb.org/pdb/results/results.do?tabtoshow=Unreleased&qrid=BF66C294
(2018) Crystal structure of HIV-1 K103N mutant reverse transcriptase in complex with non-nucleoside inhibitor K-5a2
Publicly available at the RCSB Protein Data Bank (accession no. 6C0K).

http://www.rcsb.org/pdb/results/results.do?tabtoshow=Unreleased&qrid=60EE0A57
(2018) Crystal structure of HIV-1 E138K mutant reverse transcriptase in complex with non-nucleoside inhibitor K-5a2
Publicly available at the RCSB Protein Data Bank (accession no. 6C0L).

http://www.rcsb.org/pdb/results/results.do?tabtoshow=Unreleased&qrid=5A30F676
(2018) Crystal structure of HIV-1 Y188L mutant reverse transcriptase in complex with non-nucleoside inhibitor K-5a2
Publicly available at the RCSB Protein Data Bank (accession no. 6CGF).

http://www.rcsb.org/pdb/results/results.do?tabtoshow=Unreleased&qrid=71A6FF69
(2018) Crystal structure of HIV-1 reverse transcriptase in complex with non-nucleoside inhibitor 25a
Publicly available at the RCSB Protein Data Bank (accession no. 6C0N).

http://www.rcsb.org/pdb/results/results.do?tabtoshow=Unreleased&qrid=ED459756
(2018) Crystal structure of HIV-1 K103N mutant reverse transcriptase in complex with non-nucleoside inhibitor 25a
Publicly available at the RCSB Protein Data Bank (accession no. 6C0O).

http://www.rcsb.org/pdb/results/results.do?tabtoshow=Unreleased&qrid=3D3FB131
(2018) Crystal structure of HIV-1 E138K mutant reverse transcriptase in complex with non-nucleoside inhibitor 25a
Publicly available at the RCSB Protein Data Bank (accession no. 6C0P).

http://www.rcsb.org/pdb/results/results.do?tabtoshow=Unreleased&qrid=134DF7AD
(2018) Crystal structure of HIV-1 K103N/Y181C mutant reverse transcriptase in complex with non-nucleoside inhibitor 25a
Publicly available at the RCSB Protein Data Bank (accession no. 6C0R).

http://www.rcsb.org/pdb/results/results.do?tabtoshow=Unreleased&qrid=3C348590
(2018) Crystal structure of HIV-1 reverse transcriptase V106A/F227L mutant in complex with non-nucleoside inhibitor 25a
Publicly available at the RCSB Protein Data Bank (accession no. 6DUF).

http://www.rcsb.org/pdb/results/results.do?tabtoshow=Unreleased&qrid=C8353912
(2018) Crystal structure of HIV-1 reverse transcriptase K101P mutant in complex with non-nucleoside inhibitor 25a
Publicly available at the RCSB Protein Data Bank (accession no. 6DUG).

http://www.rcsb.org/pdb/results/results.do?tabtoshow=Unreleased&qrid=105490E5
(2018) Crystal structure of HIV-1 reverse transcriptase Y181I mutant in complex with non-nucleoside inhibitor 25a
Publicly available at the RCSB Protein Data Bank (accession no. 6DUH).

http://www.rcsb.org/pdb/results/results.do?tabtoshow=Unreleased&qrid=637A3DA7

The following previously published data sets were used

1. Bauman JD
2. Patel D
3. Das K
4. Arnold E
(2013) Crystal structure of HIV-1 reverse transcriptase (RT) in complex with Rilpivirine (TMC278, Edurant), a non-nucleoside rt-inhibiting drug
Publicly available at the RCSB Protein Data Bank (accession no. 4G1Q).

https://www.rcsb.org/structure/4G1Q
1. Lansdon EB
(2010) HIV-1 Reverse Transcriptase in Complex with TMC125
Publicly available at the RCSB Protein Data Bank (accession no. 3MEC).

https://www.rcsb.org/structure/3MEC

Article and author information

Author details

Yang Yang

Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, United States

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-9061-3828
Dongwei Kang

Department of Medicinal Chemistry, Shandong University, Jinan, China

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-9232-953X
Laura A Nguyen

Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, United States

Competing interests
The authors declare that no competing interests exist.
Zachary B Smithline

Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, United States

Competing interests
The authors declare that no competing interests exist.
Christophe Pannecouque

Rega Institute for Medical Research, KU Leuven, Leuven, Belgium

Competing interests
The authors declare that no competing interests exist.
Peng Zhan

Department of Medicinal Chemistry, Shandong University, Jinan, China

For correspondence
zhanpeng1982@sdu.edu.cn

Competing interests
The authors declare that no competing interests exist.
Xinyong Liu

Department of Medicinal Chemistry, Shandong University, Jinan, China

For correspondence
xinyongl@sdu.edu.cn

Competing interests
The authors declare that no competing interests exist.
Thomas A Steitz

Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, United States

For correspondence
thomas.steitz@yale.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-3357-3505

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

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.