HIV-1 RT Inhibitors with a Novel Mechanism of Action: NNRTIs that Compete with the Nucleotide Substrate

Maga, Giovanni; Radi, Marco; Gérard, Marie-Aline; Botta, Maurizio; Ennifar, Eric

doi:10.3390/v2040880

Cited by 37 publications

(26 citation statements)

References 74 publications

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“…Our discovery now establishes NcRTI as a novel class of RT inhibitors comprised of at least two chemical classes, the indolopyridones and benzofuranopyrimidone. It should be noted that a 4-dimethylamino-6-vinylpyrimidine (DAVP) series was proposed to belong to the NcRTI class (21,22). The DAVPs were shown to be competitive with dNTPs, yet representatives from this series show a Ͼ100-fold loss in potency against NNRTI-resistant mutants K103N and Y181I.…”

Section: Discussionmentioning

confidence: 99%

Identification and Characterization of a Novel HIV-1 Nucleotide-Competing Reverse Transcriptase Inhibitor Series

Rajotte

Tremblay

Pelletier

et al. 2013

Antimicrob Agents Chemother

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tested (L100I, K103N/Y181C, V106A, or Y188L). Notably, viruses encoding K65R were hypersusceptible to inhibition by compound A. Compound A also retained full activity against viruses encoding M184V. In vitro selection for resistant virus to compound A led to the selection of a single substitution within RT: W153L. A recombinant virus encoding the RT W153L was highly resistant to compound A (fold change, 160). W153 is a highly conserved residue in HIV RT and has not been previously associated with drug resistance. In summary, a novel NcRTI series with optimized antiviral activity, minimal cross-resistance to existing RT inhibitor classes, and a distinct resistance profile has been discovered. These results further establish NcRTIs as an emerging class of antiretroviral agents.

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Section: Discussionmentioning

confidence: 99%

Identification and Characterization of a Novel HIV-1 Nucleotide-Competing Reverse Transcriptase Inhibitor Series

Rajotte

Tremblay

Pelletier

et al. 2013

Antimicrob Agents Chemother

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“…These nanogel formulations have been successfully used in cancer chemotherapy as drug delivery systems for cytotoxic nucleoside analogues. 52,53 Another avenue that we are exploring is using nucleotide-competing RT inhibitors (NcRTIs) 54 instead of NRTIs in our bifunctional inhibitor designs, since NcRTIs are distinct from the chain-terminator NRTIs and do not require any phosphorylation by cellular kinases.…”

Section: Discussionmentioning

confidence: 99%

Bifunctional Inhibition of Human Immunodeficiency Virus Type 1 Reverse Transcriptase: Mechanism and Proof-of-Concept as a Novel Therapeutic Design Strategy

Bailey

Sullivan²,

Iyidogan³

et al. 2013

J. Med. Chem.

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Human immunodeficiency virus type 1 reverse transcriptase (HIV-1 RT) is a major target for currently approved anti-HIV drugs. These drugs are divided into two classes: nucleoside and non-nucleoside reverse transcriptase inhibitors (NRTIs and NNRTIs). This study illustrates the synthesis and biochemical evaluation of a novel bifunctional RT inhibitor utilizing d4T (NRTI) and a TMC-derivative (a diarylpyrimidine NNRTI) linked via a poly(ethylene glycol) (PEG) linker. HIV-1 RT successfully incorporates the triphosphate of d4T-4PEG-TMC bifunctional inhibitor in a base-specific manner. Moreover, this inhibitor demonstrates low nanomolar potency that has 4.3-fold and 4300-fold enhancement of polymerization inhibition in vitro relative to the parent TMC-derivative and d4T, respectively. This study serves as a proof-of-concept for the development and optimization of bifunctional RT inhibitors as potent inhibitors of HIV-1 viral replication.

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“…One of the main focuses of past studies that targeted the inhibition of HIV-1 replication was reverse transcription, catalyzed by viral reverse transcriptase (RT) (13,29). Our initial data indicated that AH0109 acts at early stages of HIV-1 replication (Fig.…”

Section: Discussionmentioning

confidence: 99%

Characterization of Antiviral Activity of Benzamide Derivative AH0109 against HIV-1 Infection

Chen

Jayappa

et al. 2013

Antimicrob Agents Chemother

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In the absence of an effective vaccine against HIV-1 infection, anti-HIV-1 strategies play a major role in disease control. However, the rapid emergence of drug resistance against all currently used anti-HIV-1 molecules necessitates the development of new antiviral molecules and/or strategies against HIV-1 infection. In this study, we have identified a benzamide derivative named AH0109 that exhibits potent anti-HIV-1 activity at an 50% effective concentration of 0.7 M in HIV-1-susceptible CD4 ؉ C8166 T cells. Mechanistic analysis revealed that AH0109 significantly inhibits both HIV-1 reverse transcription and viral cDNA nuclear import. Furthermore, our infection experiments indicated that AH0109 is capable of disrupting the replication of HIV-1 strains that are resistant to the routinely used anti-HIV-1 drugs zidovudine, lamivudine, nevirapine, and raltegravir. Together, these findings provide evidence for a newly identified antiviral molecule that can potentially be developed as an anti-HIV-1 agent.

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HIV-1 RT Inhibitors with a Novel Mechanism of Action: NNRTIs that Compete with the Nucleotide Substrate

Cited by 37 publications

References 74 publications

Identification and Characterization of a Novel HIV-1 Nucleotide-Competing Reverse Transcriptase Inhibitor Series

Identification and Characterization of a Novel HIV-1 Nucleotide-Competing Reverse Transcriptase Inhibitor Series

Bifunctional Inhibition of Human Immunodeficiency Virus Type 1 Reverse Transcriptase: Mechanism and Proof-of-Concept as a Novel Therapeutic Design Strategy

Characterization of Antiviral Activity of Benzamide Derivative AH0109 against HIV-1 Infection

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