Complex interplay of kinetic factors governs the synergistic properties of HIV-1 entry inhibitors

Ahn, Koree; Root, Michael J.

doi:10.1074/jbc.m117.791731

Cited by 17 publications

(23 citation statements)

References 73 publications

(126 reference statements)

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“…Previous studies have described multifaceted mechanisms of HIV-1 resistance to peptide fusion inhibitors, including small amino acid-mediated reduced contact, large amino acidmediated steric obstruction, acidic amino acid-mediated electrostatic repulsion, basic amino acid-mediated electrostatic attraction, and disruption of hydrogen bonds and hydrophobic contacts (48). It was also proposed that kinetically restricted entry inhibitors have reduced sensitivity to affinity-disrupting resistance mutations (49,50). Here, we investigated the underlying mechanisms of SFT-induced resistance mutations from two aspects: their effects on the binding stability of inhibitors and on the functionality of viral Env glycoprotein.…”

Section: Hiv-1 Resistance To Sifuvirtidementioning

confidence: 99%

Molecular mechanism of HIV-1 resistance to sifuvirtide, a clinical trial–approved membrane fusion inhibitor

Ding

Liu

et al. 2018

Journal of Biological Chemistry

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Host cell infection with HIV-1 requires fusion of viral and cell membranes. Sifuvirtide (SFT) is a peptide-based HIV-1 fusion inhibitor approved for phase III clinical trials in China. Here, we focused on characterizing HIV-1 variants highly resistant to SFT to gain insight into the molecular resistance mechanism. Three primary substitutions (V38A, A47I, and Q52R) located at the inhibitor-binding site of HIV-1's envelope protein (Env) and one secondary substitution (N126K) located at the C-terminal heptad repeat region of the viral protein gp41, which is part of the envelope, conferred high SFT resistance and cross-resistance to the anti-HIV-1 drug T20 and the template peptide C34. Interestingly, SFT's resistance profile could be dramatically improved with an M-T hook structure-modified SFT (MTSFT) and with short-peptide inhibitors that mainly target the gp41 pocket (2P23 and its lipid derivative LP-19). We found that the V38A and Q52R substitutions reduce the binding stabilities of SFT, C34, and MTSFT, but they had no effect on the binding of 2P23 and LP-19; in sharp contrast, the A47I substitution enhanced fusion inhibitor binding. Furthermore, the primary resistance substitutions impaired Env-mediated membrane fusion and cell entry and changed the conformation of the gp41 core structure. Importantly, whereas the V38A and Q52R substitutions disrupted the N-terminal helix of gp41, a single A47I substitution greatly enhanced its thermostability. Taken together, our results provide crucial structural insights into the mechanism of HIV-1 resistance to gp41-dependent fusion inhibitors, which may inform the development of additional anti-HIV drugs.

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Section: Hiv-1 Resistance To Sifuvirtidementioning

confidence: 99%

Molecular mechanism of HIV-1 resistance to sifuvirtide, a clinical trial–approved membrane fusion inhibitor

Ding

Liu

et al. 2018

Journal of Biological Chemistry

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“…These results clearly support the capacity of compound #7 to inhibit HIV and synergize with selected clinical drugs, including reverse transcriptase inhibitors and integrase inhibitors, in HIV-exposed cells. Thus they encourage future studies addressing the physiological relevance of the synergisms and detailed analysis of potentially complex combinatorial compound effects 24,25 .…”

Section: Scientific Reports |mentioning

confidence: 97%

Potent inhibition of HIV replication in primary human cells by novel synthetic polyketides inspired by Aureothin

Herrmann

Roesner²,

Werner

et al. 2020

Sci Rep

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overcoming the global health threat of HiV infection requires continuous pipelines of novel drug candidates. We identified the γ-pyrone polyketides Aureothin/neoaureothin as potent hits by anti-HiV screening of an extensive natural compound collection. total synthesis of a structurally diverse group of Aureothin-derivatives successfully identified a lead compound (#7) superior to Aureothin that combines strong anti-HIV activity (IC 90 <45 nM), photostability and improved cell safety. Compound #7 inhibited de novo virus production from integrated proviruses by blocking the accumulation of HiV RnAs that encode the structural components of virions and include viral genomic RnAs. thus, the mode-of-action displayed by compound #7 is different from those of all current clinical drugs. Proteomic analysis indicated that compound #7 does not affect global protein expression in primary blood cells and may modulate cellular pathways linked to HIV infection. Compound #7 inhibited multiple HIV genotypes, including HIV-type 1 and 2 and synergistically inhibited HIV in combination with clinical reverse transcriptase and integrase inhibitors. We conclude that compound #7 represents a promising new class of HIV inhibitors that will facilitate the identification of new virus-host interactions exploitable for antiviral attack and holds promise for further drug development.

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“…Combination drug therapy is an advancing field of research in oncology, anesthesiology and immunology (Mao et al, 2011;Dahl et al, 2014;Bansal et al, 2014;Hu et al, 2016;Ahn & Root, 2017;Eser & Jänne, 2018).…”

Section: Introductionmentioning

confidence: 99%

“…This effect-based strategy permits an additivity concept according to the addition rule of probabilities. Two agents which act on different components in a biochemical cascade can be modeled in this mutually non-exclusive way (e.g., the HIV-1 entry inhibitors CoRA and FI (Ahn & Root, 2017)). However, the implicit assumption of stochastic independence does not hold in case of drugs that act through a similar mechanism.…”

Section: Introductionmentioning

confidence: 99%

Comparison of null models for combination drug therapy reveals Hand model as biochemically most plausible

Sinzger

Vanhoefer

Loos

et al. 2018

Preprint

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Null models for the effect of combination therapies are widely used to evaluate synergy and antagonism of drugs. Due to the relevance of null models, their suitability is continuously discussed. Here, we contribute to the discussion by investigating the properties of five null models. Our study includes the model proposed by David J. Hand, which we refer to as Hand model. The Hand model has been introduced almost 20 years ago but hardly was used and studied. We show that the Hand model generalizes the principle of dose equivalence compared to the Loewe model and resolves the ambiguity of the Tallarida model. This provides a solution to the persisting conflict about the compatibility of two essential model properties: the sham combination principle and the principle of dose equivalence. By embedding several null models into a common framework, we shed light in their biochemical validity and provide indications that the Hand model is biochemically most plausible. We illustrate the practical implications and differences between null models by examining differences of null models on published data.

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Complex interplay of kinetic factors governs the synergistic properties of HIV-1 entry inhibitors

Cited by 17 publications

References 73 publications

Molecular mechanism of HIV-1 resistance to sifuvirtide, a clinical trial–approved membrane fusion inhibitor

Molecular mechanism of HIV-1 resistance to sifuvirtide, a clinical trial–approved membrane fusion inhibitor

Potent inhibition of HIV replication in primary human cells by novel synthetic polyketides inspired by Aureothin

Comparison of null models for combination drug therapy reveals Hand model as biochemically most plausible

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