Discovery of a small-molecule antiviral targeting the HIV-1 matrix protein

Zentner, Isaac; Sierra, Luz-Jeannette; Maciunas, Lina J.; Vinnik, Andrei; Федичев, П. О.; Mankowski, Marie K.; Ptak, Roger G.; Martín-García, Julio; Simon, Chantal

doi:10.1016/j.bmcl.2012.11.041

Cited by 27 publications

(28 citation statements)

References 51 publications

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“…The MA domain is a conserved domain of Gag across several retroviruses, thus we expect our conclusions to also provide insight to understand the mechanism of binding in other viral systems (62). Fundamental understanding of the membrane targeting mechanism of MA can offer new perspectives for inhibitor-based anti-retroviral treatments (63) and expand the general understanding about peripheral protein interactions with membranes and corresponding implications in macromolecular assembly.…”

Section: Methodsmentioning

confidence: 66%

Binding Mechanism of the Matrix Domain of HIV-1 Gag on Lipid Membranes

Monje-Galvan

Voth

2020

Preprint

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Aggregation of the HIV-1 Gag protein onto the plasma membrane (PM) enables viral budding and infection propagation. Gag assembly at the membrane interface is mediated by its matrix domain (MA), the Myristoylated (Myr) N-terminus. MA targets the PM through electrostatic interactions, mainly at its highly-basic-region (HBR). The mechanism of Myr insertion and its role in proteinmembrane dynamics remains unclear. Using all-atom molecular dynamics, we examined an MA unit in the vicinity of lipid bilayers that model different characteristics of the PM. Interaction with PIP2 and PS lipids is highly favored around the HBR, and is enough to keep the protein bound. Additionally, we simulated three MA units near our bilayers and quantified the collective effects of free monomers vs. formed trimers on Myr insertion events. Micro-second-long trajectories allowed us to observe Myr insertion, propose a mechanism, quantify specific interactions with lipids, and examine the response of the local membrane environment.

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Section: Methodsmentioning

confidence: 66%

Binding Mechanism of the Matrix Domain of HIV-1 Gag on Lipid Membranes

Monje-Galvan

Voth

2020

Preprint

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“…21,22 MA might be also a useful target for inhibition of HIV-1 replication. 23 According to several previous reports, MA-derived peptides such as MA (31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45), MA(41-55) and MA(47-59) show anti-HIV activity, 24,25 and MA(61-75) and MA(71-85) inhibit MA dimerization, which is an essential step in the formation of the virion shell. 26 However, whether these MA peptides can penetrate cell membranes was not described in the above reports.…”

Section: Introductionmentioning

confidence: 93%

Anti-HIV screening for cell-penetrating peptides using chloroquine and identification of anti-HIV peptides derived from matrix proteins

Mizuguchi

Ohashi

Nomura

et al. 2015

Bioorganic & Medicinal Chemistry

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“…The structures of both VSV and LABV M proteins have been solved [146], fueling the mechanistic appreciation of M assembly and opening a door towards structure-guided drug design against specific M microdomains. Attractive antiviral targets include M domains involved in M homo-oligomerization, interaction with host proteins, or required for binding to the viral G protein [17,18,70,125,126,[146][147][148][149][150][151].…”

Section: Direct-acting Antiviralsmentioning

confidence: 99%

Status of antiviral therapeutics against rabies virus and related emerging lyssaviruses

Pont

Plemper

Schnell

2019

Current Opinion in Virology

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Rabies virus (RABV) constitutes a major social and economic burden associated with 60,000 deaths annually worldwide. Although pre-and post-exposure treatment options are available, they are efficacious only when initiated prior to the onset of clinical symptoms. Aggravating the problem, the current RABV vaccine does not cross-protect against the emerging zoonotic phylogroup II lyssaviruses. A requirement for an uninterrupted cold chain and high cost of the immunoglobulin component of rabies prophylaxis generate an unmet need for the development of RABV-specific antivirals. We discuss desirable anti-RABV drug profiles, past efforts to address the problem and inhibitor candidates identified, and examine how the rapidly expanding structural insight into RABV protein organization has illuminated novel druggable target candidates and paved the way to structure-aided drug optimization. Special emphasis is given to the viral RNAdependent RNA polymerase complex as a promising target for direct-acting broad-spectrum RABV inhibitors.

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Discovery of a small-molecule antiviral targeting the HIV-1 matrix protein

Cited by 27 publications

References 51 publications

Binding Mechanism of the Matrix Domain of HIV-1 Gag on Lipid Membranes

Binding Mechanism of the Matrix Domain of HIV-1 Gag on Lipid Membranes

Anti-HIV screening for cell-penetrating peptides using chloroquine and identification of anti-HIV peptides derived from matrix proteins

Status of antiviral therapeutics against rabies virus and related emerging lyssaviruses

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