Crystal Structures of HIV-1 Reverse Transcriptase with Picomolar Inhibitors Reveal Key Interactions for Drug Design

Frey, Kathleen M.; Bollini, Mariela; Mislak, Andrea C.; Cisneros, José A.; Gallardo‐Macias, Ricardo; Jorgensen, William L.; Anderson, Karen S.

doi:10.1021/ja3092642

Cited by 49 publications

(101 citation statements)

References 18 publications

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“…2). The overall conformation of compound II and the binding pocket is very similar to what we have observed previously with other RT:catechol diether complexes (Frey et al, 2012Lee et al, 2013Lee et al, , 2014 (Fig. 3).…”

Section: Resultssupporting

confidence: 86%

Section: Methodsmentioning

confidence: 99%

“…Recombinant RT52A enzyme was expressed and purified to homogeneity using methods described previously (Das Frey et al, 2012). Crystals of RT52A in the complex with compound II were prepared using similar methods as for catechol diether complexes (Frey et al, 2012). The final optimized condition for crystal growth consisted of 18% (w/v) polyethylene glycol 8000, 100 mM ammonium sulfate, 15 mM magnesium sulfate, 5 mM spermine, and 50 mM 4-morpholineethanesulfonic acid (pH 6.0).…”

Section: Methodsmentioning

confidence: 99%

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

Kudalkar

Beloor

Chan

et al. 2017

Molecular Pharmacology

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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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Section: Resultssupporting

confidence: 86%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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

Kudalkar

Beloor

Chan

et al. 2017

Molecular Pharmacology

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“…Introduction of fluorine atom or fluorinated moieties into bioactive molecules has become one kind of widespread and important drug optimization strategy, which has attracted considerable attention from medicinal chemists [10][11][12][13][14][15][16][17][18][19][20]. The increased anti-HIV activity of fluorinated NNRTIs has also been well documented in WO2014072419.…”

Section: Efficacious Roles Of the Fluorine Pharmacophore In Nnrtismentioning

confidence: 99%

Novel fluorine-containing DAPY derivatives as potent HIV-1 NNRTIs: a patent evaluation of WO2014072419

Meng¹,

Liu²,

Huang³

et al. 2015

Expert Opinion on Therapeutic Patents

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Diarylpyrimidine (DAPY) derivatives, one family of HIV non-nucleoside reverse transcriptase (RT) inhibitors (NNRTIs) with superior activities against wild-type (WT) HIV-1 and NNRTI-resistant strains, have attracted much attention in the past decade. A series of DAPY derivatives featuring a fluorine atom on the central ring were reported as novel NNRTIs in the patent WO2014072419. Some compounds exhibited robust potency against both WT and mutant strains, which were approximately equal to or higher than those of the reference drug TMC120. Moreover, it has become evident that fluorinated molecules have a remarkable record in many other potent NNRTIs. Thus, this survey provides a sampling of renowned fluorinated NNRTIs and their mode of action, with an analysis clarifying the functional roles and impact of fluorine substitution on antiviral potency. We envision that fluorinated NNRTIs will play a continuing role in affording anti-HIV drug candidates for therapeutic applications.

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“…IC 50 values were determined for rilpivirine and compounds 1−3 using methods described previously. 22,28 Activity and inhibition assays were determined for both RT Table 2. Kinetic Characterization of dGTP Misincorporation Opposite dT for RT (WT) and RT (K101P) (Table 1).…”

mentioning

confidence: 99%

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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Crystal Structures of HIV-1 Reverse Transcriptase with Picomolar Inhibitors Reveal Key Interactions for Drug Design

Cited by 49 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

Novel fluorine-containing DAPY derivatives as potent HIV-1 NNRTIs: a patent evaluation of WO2014072419

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

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