Picomolar Inhibitors of HIV-1 Reverse Transcriptase: Design and Crystallography of Naphthyl Phenyl Ethers

Lee, Won‐Gil; Frey, Kathleen M.; Gallardo‐Macias, Ricardo; Spasov, Krasimir A.; Bollini, Mariela; Anderson, Karen S.; Jorgensen, William L.

doi:10.1021/ml5003713

Cited by 35 publications

(93 citation statements)

References 18 publications

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“…The synthetic procedures for preparation of compounds I and II have been previously described in detail (Bollini et al, 2011;Lee et al, 2014).…”

Section: Methodsmentioning

confidence: 99%

“…High-resolution data sets for the best diffracting crystals were processed with HKL2000 (Otwinowski and Minor, 1997). To obtain phases, molecular replacement was performed with Phaser (McCoy et al, 2007) using a previously determined RT:NNRTI complex (Protein Data Bank code: 4WE1) as the search model (Lee et al, 2014). The software program Coot (Emsley et al, 2010) was used for model building into the electron density.…”

Section: Methodsmentioning

confidence: 99%

“…These compounds belong to a potent class of inhibitors known as catechol diethers, which possess better aqueous solubility, low cytotoxicity, and increased potency toward wild-type (WT) and resistant strains of HIV-1 (Lee et al, 2013(Lee et al, , 2014. Compound I demonstrates picomolar activity (310 pM) against WT RT and low nanomolar activity toward clinically challenging variants (Lee et al, 2014), likely resulting from its molecular flexibility at the NNRTI binding pocket . Compound II possesses low nanomolar potency (1.9 nM) for WT RT and has very low cytotoxicity (.100 mM) (Lee et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

“…Compound I demonstrates picomolar activity (310 pM) against WT RT and low nanomolar activity toward clinically challenging variants (Lee et al, 2014), likely resulting from its molecular flexibility at the NNRTI binding pocket . Compound II possesses low nanomolar potency (1.9 nM) for WT RT and has very low cytotoxicity (.100 mM) (Lee et al, 2014). These encouraging findings prompted us to further investigate compounds I and II as potential anti-HIV drug candidates.…”

Section: Introductionmentioning

confidence: 99%

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Structural and Preclinical Studies of Computationally Designed Non-Nucleoside Reverse Transcriptase Inhibitors for Treating HIV infection

et al. 2017

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The clinical benefits of HIV-1 non-nucleoside reverse transcriptase (RT) inhibitors (NNRTIs) are hindered by their unsatisfactory pharmacokinetic (PK) properties along with the rapid development of drug-resistant variants. However, the clinical efficacy of these inhibitors can be improved by developing compounds with enhanced pharmacological profiles and heightened antiviral activity. We used computational and structure-guided design to develop two next-generation NNRTI drug candidates, compounds I and II, which are members of a class of catechol diethers. We evaluated the preclinical potential of these compounds in BALB/c mice because of their high solubility (510 mg/ml for compound I and 82.9 mg/ml for compound II), low cytotoxicity, and enhanced antiviral activity against wild-type (WT) HIV-1 RT and resistant variants. Additionally, crystal structures of compounds I and II with WT RT suggested an optimal binding to the NNRTI binding pocket favoring the high anti-viral potency. A single intraperitoneal dose of compounds I and II exhibited a prolonged serum residence time of 48 hours and concentration maximum (C max ) of 4000-to 15,000-fold higher than their therapeutic/effective concentrations. These C max values were 4-to 15-fold lower than their cytotoxic concentrations observed in MT-2 cells. Compound II showed an enhanced area under the curve (0-last) and decreased plasma clearance over compound I and efavirenz, the standard of care NNRTI. Hence, the overall (PK) profile of compound II was excellent compared with that of compound I and efavirenz. Furthermore, both compounds were very well tolerated in BALB/c mice without any detectable acute toxicity. Taken together, these data suggest that compounds I and II possess improved anti-HIV-1 potency, remarkable in vivo safety, and prolonged in vivo circulation time, suggesting strong potential for further development as new NNRTIs for the potential treatment of HIV infection.

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“…The synthetic procedures for preparation of compounds I and II have been previously described in detail (Bollini et al, 2011;Lee et al, 2014).…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Structural and Preclinical Studies of Computationally Designed Non-Nucleoside Reverse Transcriptase Inhibitors for Treating HIV infection

et al. 2017

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“…In an improvement over the results from an MTT assay used previously, 21,23,25 RT variants with Y181C are also susceptible to 1−3 in the low nanomolar range. Compounds 1 and 2 are less effective against variants containing the K103N mutation, whereas 3 retains potency 4-fold greater than rilpivirine.…”

mentioning

confidence: 69%

Potent Inhibitors Active against HIV Reverse Transcriptase with K101P, a Mutation Conferring Rilpivirine Resistance

Gray

Frey

Laskey

et al. 2015

ACS Med. Chem. Lett.

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Catechol diether compounds have nanomolar antiviral and enzymatic activity against HIV with reverse transcriptase (RT) variants containing K101P, a mutation that confers high-level resistance to FDA-approved non-nucleoside inhibitors efavirenz and rilpivirine. Kinetic data suggests that RT (K101P) variants are as catalytically fit as wild-type and thus can potentially increase in the viral population as more antiviral regimens include efavirenz or rilpivirine. Comparison of wild-type structures and a new crystal structure of RT (K101P) in complex with a leading compound confirms that the K101P mutation is not a liability for the catechol diethers while suggesting that key interactions are lost with efavirenz and rilpivirine.

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Long‐acting and extended‐release implant and nanoformulations with a synergistic antiretroviral two‐drug combination controls HIV‐1 infection in a humanized mouse model

Beloor

Kudalkar

Buzzelli

et al. 2021

Bioengineering & Transla Med

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Picomolar Inhibitors of HIV-1 Reverse Transcriptase: Design and Crystallography of Naphthyl Phenyl Ethers

Cited by 35 publications

References 18 publications

Structural and Preclinical Studies of Computationally Designed Non-Nucleoside Reverse Transcriptase Inhibitors for Treating HIV infection

Structural and Preclinical Studies of Computationally Designed Non-Nucleoside Reverse Transcriptase Inhibitors for Treating HIV infection

Potent Inhibitors Active against HIV Reverse Transcriptase with K101P, a Mutation Conferring Rilpivirine Resistance

Long‐acting and extended‐release implant and nanoformulations with a synergistic antiretroviral two‐drug combination controls HIV‐1 infection in a humanized mouse model

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