Covalent Inhibitors for Eradication of Drug-resistant HIV-1 Reverse Transcriptase: From Design to Protein Crystallography

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2017 Aug 23

PMID 28827354

Citations 19

Authors

Albert H Chan

Won-Gil Lee

Krasimir A Spasov

Jose A Cisneros

Shalley N Kudalkar

Zaritza O Petrova

Amanda B Buckingham

Karen S Anderson

William L Jorgensen

Affiliations

Soon will be listed here.

Abstract

Development of resistance remains a major challenge for drugs to treat HIV-1 infections, including those targeting the essential viral polymerase, HIV-1 reverse transcriptase (RT). Resistance associated with the Tyr181Cys mutation in HIV-1 RT has been a key roadblock in the discovery of nonnucleoside RT inhibitors (NNRTIs). It is the principal point mutation that arises from treatment of HIV-infected patients with nevirapine, the first-in-class drug still widely used, especially in developing countries. We report covalent inhibitors of Tyr181Cys RT (CRTIs) that can completely knock out activity of the resistant mutant and of the particularly challenging Lys103Asn/Tyr181Cys variant. Conclusive evidence for the covalent modification of Cys181 is provided from enzyme inhibition kinetics, mass spectrometry, protein crystallography, and antiviral activity in infected human T-cell assays. The CRTIs are also shown to be selective for Cys181 and have lower cytotoxicity than the approved NNRTI drugs efavirenz and rilpivirine.

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References

Sebaaly J, Kelley D . Single-Tablet Regimens for the Treatment of HIV-1 Infection. Ann Pharmacother. 2016; 51(4):332-344. DOI: 10.1177/1060028016682531. View

Petersen L, Jessen C, Pedersen E, Nielsen C . Synthesis and evaluation of new potential HIV-1 non-nucleoside reverse transcriptase inhibitors. New analogues of MKC-442 containing Michael acceptors in the C-6 position. Org Biomol Chem. 2003; 1(20):3541-5. DOI: 10.1039/b307800k. View

Lee W, Chan A, Spasov K, Anderson K, Jorgensen W . Design, Conformation, and Crystallography of 2-Naphthyl Phenyl Ethers as Potent Anti-HIV Agents. ACS Med Chem Lett. 2016; 7(12):1156-1160. PMC: 5151141. DOI: 10.1021/acsmedchemlett.6b00390. View

Gray W, Frey K, Laskey S, Mislak A, Spasov K, Lee W . Potent Inhibitors Active against HIV Reverse Transcriptase with K101P, a Mutation Conferring Rilpivirine Resistance. ACS Med Chem Lett. 2015; 6(10):1075-9. PMC: 4601059. DOI: 10.1021/acsmedchemlett.5b00254. View

Janssen P, Lewi P, Arnold E, Daeyaert F, De Jonge M, Heeres J . In search of a novel anti-HIV drug: multidisciplinary coordination in the discovery of 4-[[4-[[4-[(1E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2- pyrimidinyl]amino]benzonitrile (R278474, rilpivirine). J Med Chem. 2005; 48(6):1901-9. DOI: 10.1021/jm040840e. View

Emsley P, Lohkamp B, Scott W, Cowtan K . Features and development of Coot. Acta Crystallogr D Biol Crystallogr. 2010; 66(Pt 4):486-501. PMC: 2852313. DOI: 10.1107/S0907444910007493. View

Lin T, Luo M, Liu M, Pai S, Dutschman G, Cheng Y . Antiviral activity of 2',3'-dideoxy-beta-L-5-fluorocytidine (beta-L-FddC) and 2',3'-dideoxy-beta-L-cytidine (beta-L-ddC) against hepatitis B virus and human immunodeficiency virus type 1 in vitro. Biochem Pharmacol. 1994; 47(2):171-4. DOI: 10.1016/0006-2952(94)90002-7. View

Basavapathruni A, Vingerhoets J, de Bethune M, Chung R, Bailey C, Kim J . Modulation of human immunodeficiency virus type 1 synergistic inhibition by reverse transcriptase mutations. Biochemistry. 2006; 45(23):7334-40. DOI: 10.1021/bi052362v. View

Singh J, Petter R, Baillie T, Whitty A . The resurgence of covalent drugs. Nat Rev Drug Discov. 2011; 10(4):307-17. DOI: 10.1038/nrd3410. View

10.

Das K, Bauman J, Clark Jr A, Frenkel Y, Lewi P, Shatkin A . High-resolution structures of HIV-1 reverse transcriptase/TMC278 complexes: strategic flexibility explains potency against resistance mutations. Proc Natl Acad Sci U S A. 2008; 105(5):1466-71. PMC: 2234167. DOI: 10.1073/pnas.0711209105. View

11.

Ray A, Yang Z, Chu C, Anderson K . Novel use of a guanosine prodrug approach to convert 2',3'-didehydro-2',3'-dideoxyguanosine into a viable antiviral agent. Antimicrob Agents Chemother. 2002; 46(3):887-91. PMC: 127498. DOI: 10.1128/AAC.46.3.887-891.2002. View

12.

Frey K, Puleo D, Spasov K, Bollini M, Jorgensen W, Anderson K . Structure-based evaluation of non-nucleoside inhibitors with improved potency and solubility that target HIV reverse transcriptase variants. J Med Chem. 2015; 58(6):2737-45. PMC: 4378236. DOI: 10.1021/jm501908a. View

13.

Morin A, Eisenbraun B, Key J, Sanschagrin P, Timony M, Ottaviano M . Collaboration gets the most out of software. Elife. 2013; 2:e01456. PMC: 3771563. DOI: 10.7554/eLife.01456. View

14.

Bollini M, Gallardo-Macias R, Spasov K, Tirado-Rives J, Anderson K, Jorgensen W . Optimization of benzyloxazoles as non-nucleoside inhibitors of HIV-1 reverse transcriptase to enhance Y181C potency. Bioorg Med Chem Lett. 2013; 23(4):1110-3. PMC: 3561933. DOI: 10.1016/j.bmcl.2012.11.115. View

15.

Lee W, Frey K, Gallardo-Macias R, Spasov K, Bollini M, Anderson K . Picomolar Inhibitors of HIV-1 Reverse Transcriptase: Design and Crystallography of Naphthyl Phenyl Ethers. ACS Med Chem Lett. 2014; 5(11):1259-62. PMC: 4233359. DOI: 10.1021/ml5003713. View

16.

Jorgensen W, Bollini M, Thakur V, Domaoal R, Spasov K, Anderson K . Efficient discovery of potent anti-HIV agents targeting the Tyr181Cys variant of HIV reverse transcriptase. J Am Chem Soc. 2011; 133(39):15686-96. PMC: 3183387. DOI: 10.1021/ja2058583. View

17.

de Bethune M . Non-nucleoside reverse transcriptase inhibitors (NNRTIs), their discovery, development, and use in the treatment of HIV-1 infection: a review of the last 20 years (1989-2009). Antiviral Res. 2009; 85(1):75-90. DOI: 10.1016/j.antiviral.2009.09.008. View

18.

Otwinowski Z, Minor W . Processing of X-ray diffraction data collected in oscillation mode. Methods Enzymol. 1997; 276:307-26. DOI: 10.1016/S0076-6879(97)76066-X. View

19.

Adams P, Afonine P, Bunkoczi G, Chen V, Davis I, Echols N . PHENIX: a comprehensive Python-based system for macromolecular structure solution. Acta Crystallogr D Biol Crystallogr. 2010; 66(Pt 2):213-21. PMC: 2815670. DOI: 10.1107/S0907444909052925. View

20.

Gubernick S, Felix N, Lee D, Xu J, Hamad B . The HIV therapy market. Nat Rev Drug Discov. 2016; 15(7):451-2. DOI: 10.1038/nrd.2016.69. View