Evidence map›Paper›PMID 31281023›Full record

ArticleBioorganic & medicinal chemistry letters2019

Molecular and cellular studies evaluating a potent 2-cyanoindolizine catechol diether NNRTI targeting wildtype and Y181C mutant HIV-1 reverse transcriptase.

Tomoaki Sasaki, Zira T K Gannam, Shalley N Kudalkar, Kathleen M Frey, Won-Gil Lee, Krasimir A Spasov, William L Jorgensen, Karen S Anderson

Abstract readLetter
PubMed Full text at PMC Publisher
In one paragraph

Article in Bioorganic & medicinal chemistry letters, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.

0numbers the graph read from it
0cells of the map it votes in
4citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

4 citing papers in PubMed.

  1. Review
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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

8 authors.

Tomoaki SasakiDepartment of Pharmacology, Yale University, 333 Cedar Street, New Haven, CT 06520, United States.
Zira T K GannamDepartment of Pharmacology, Yale University, 333 Cedar Street, New Haven, CT 06520, United States.
Shalley N KudalkarDepartment of Pharmacology, Yale University, 333 Cedar Street, New Haven, CT 06520, United States.
Kathleen M FreyDepartment of Pharmacology, Yale University, 333 Cedar Street, New Haven, CT 06520, United States.
Won-Gil LeeDepartment of Chemistry, Yale University, 225 Prospect Street, PO Box 208107, New Haven, CT 06520, United States.
Krasimir A SpasovDepartment of Pharmacology, Yale University, 333 Cedar Street, New Haven, CT 06520, United States.
William L JorgensenDepartment of Chemistry, Yale University, 225 Prospect Street, PO Box 208107, New Haven, CT 06520, United States.
Karen S AndersonDepartment of Pharmacology, Yale University, 333 Cedar Street, New Haven, CT 06520, United States; Department of Molecular Biophysics and Biochemistry, Yale University, 333 Cedar Street, New Haven, CT 06520, United States. Electronic address: karen.anderson@yale.edu.

Funding

MECHANISM AND INHIBITION OF HIV REVERSE TRANSCRIPTASER01GM049551 · NIGMS · YALE UNIVERSITY · PI ANDERSON, KAREN S. · 1993 to 2019
$9.0M
COMPUTER-AIDED DESIGN OF ANTIHIV DRUGSR01AI044616 · NIAID · YALE UNIVERSITY · PI JORGENSEN, WILLIAM L. · 1999 to 2022
$7.7M
Predoctoral Training Program in VirologyT32AI055403 · NIAID · YALE UNIVERSITY · PI KUMAR, PRITI, MOTHES, WALTHER H · 2003 to 2024
$3.6M
Structure activity and structure property relationships for novel anti-HIV agentsF32AI104334 · NIAID · YALE UNIVERSITY · PI FREY, KATHLEEN MARY · 2013 to 2015
$140k
Biochemical and Functional Characterization of the Mutagenic Cytidine Deaminase APOBEC3B in the contextof Squamous Cell Lung CarcinomaF31CA203254 · NCI · YALE UNIVERSITY · PI SASAKI, TOMOAKI · 2016 to 2018
$96k
NCI NIH HHS F31 CA203254NIAID NIH HHS F32 AI104334NIAID NIH HHS R01 AI044616NIAID NIH HHS T32 AI055403NIGMS NIH HHS R01 GM049551
6 · The paper itself

Abstract

The development of efficacious NNRTIs for HIV/AIDS therapy is commonly met with the emergence of drug resistant strains, including the Y181C variant. Using a computationally-guided approach, we synthesized the catechol diether series of NNRTIs, which display sub-nanomolar potency in cellular assays. Among the most potent were a series of 2-cyanoindolizine substituted catechol diethers, including Compound 1. We present here a thorough evaluation of this compound, including biochemical, cellular, and structural studies. The compound demonstrates low nanomolar potency against both WT and Y181C HIV-1 RT in in vitro and cellular assays. Our crystal structures of both the wildtype and mutant forms of RT in complex with Compound 1 allow the interrogation of this compound's features that allow it to maintain strong efficacy against the drug resistant mutant. Among these are compensatory shifts in the NNRTI binding pocket, persistence of multiple hydrogen bonds, and van der Waals contacts throughout the binding site. Further, the fluorine at the C6 position of the indolizine moiety makes multiple favorable interactions with both RT forms. The present study highlights the indolizine-substituted catechol diether class of NNRTIs as promising therapeutic candidates possessing optimal pharmacological properties and significant potency against multiple RT variants.

Indexed as

Anti-HIV AgentsCatecholsDrug DesignHIV Reverse TranscriptaseMolecular StructureReverse Transcriptase InhibitorsAnti-HIV AgentsCatecholsHIV Reverse Transcriptasereverse transcriptase, Human immunodeficiency virus 1Reverse Transcriptase InhibitorsComputational drug designDrug resistanceHIVNNRTIReverse transcriptaseStructure-based drug design

Identifiers

PMID31281023
PMCPMC6690785

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.