Identification of a Potential Inhibitor of the FIV p24 Capsid Protein and Characterization of Its Binding Site

Long, Mathieu; Cantrelle, François-Xavier; Robert, Xavier; Boll, Emmanuelle; Sierra, Natalia; Gouet, Patrice; Hanoulle, Xavier; Álvarez, Guzmán; Guillon, Christophe

doi:10.1021/acs.biochem.1c00228

Cited by 4 publications

(12 citation statements)

References 73 publications

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“…We have recently demonstrated the binding and inhibitory effect of 696 on FIV capsid assembly in vitro [ 27 ]. Thus, we investigated the interaction of 696 with HIV-1 CA by microscale thermophoresis (MST).…”

Section: Resultsmentioning

confidence: 99%

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Identification of 2-(4-N,N-Dimethylaminophenyl)-5-methyl-1-phenethyl-1H-benzimidazole targeting HIV-1 CA capsid protein and inhibiting HIV-1 replication in cellulo

Álvarez

Pul

Robert

et al. 2022

BMC Pharmacol Toxicol

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The capsid (CA) subunit of the HIV-1 Gag polyprotein is involved in several steps of the viral cycle, from the assembly of new viral particles to the protection of the viral genome until it enters into the nucleus of newly infected cells. As such, it represents an interesting therapeutic target to tackle HIV infection. In this study, we screened hundreds of compounds with a low cost of synthesis for their ability to interfere with Gag assembly in vitro. Representatives of the most promising families of compounds were then tested for their ability to inhibit HIV-1 replication in cellulo. From these molecules, a hit compound from the benzimidazole family with high metabolic stability and low toxicity, 2-(4-N,N-dimethylaminophenyl)-5-methyl-1-phenethyl-1H-benzimidazole (696), appeared to block HIV-1 replication with an IC50 of 3 µM. Quantitative PCR experiments demonstrated that 696 does not block HIV-1 infection before the end of reverse transcription, and molecular docking confirmed that 696 is likely to bind at the interface between two monomers of CA and interfere with capsid oligomerization. Altogether, 696 represents a promising lead molecule for the development of a new series of HIV-1 inhibitors.

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Section: Resultsmentioning

confidence: 99%

“…The chemical synthesis of these molecules followed the previously reported procedures [ 28 , 30 , 33 , 38 , 39 ]. Synthesis and in-depth characterization of the two compounds 696 [ 27 ] and 314, which are thoroughly analyzed in this study, are available as supporting information.…”

Section: Methodsmentioning

confidence: 99%

Identification of 2-(4-N,N-Dimethylaminophenyl)-5-methyl-1-phenethyl-1H-benzimidazole targeting HIV-1 CA capsid protein and inhibiting HIV-1 replication in cellulo

Álvarez

Pul

Robert

et al. 2022

BMC Pharmacol Toxicol

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“…Compound 696 A screening of an in-house library of 400 compounds identified a feline immunodeficiency virus (FIV) assembly inhibitor, named 696 (Table 1) [73]. The authors also identified the binding pocket within FIV CA where 696 binds.…”

Section: Ck026 and I-xw-053mentioning

confidence: 99%

Targeting the Virus Capsid as a Tool to Fight RNA Viruses

Hozáková

Vokatá

Ruml

et al. 2022

Viruses

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Several strategies have been developed to fight viral infections, not only in humans but also in animals and plants. Some of them are based on the development of efficient vaccines, to target the virus by developed antibodies, others focus on finding antiviral compounds with activities that inhibit selected virus replication steps. Currently, there is an increasing number of antiviral drugs on the market; however, some have unpleasant side effects, are toxic to cells, or the viruses quickly develop resistance to them. As the current situation shows, the combination of multiple antiviral strategies or the combination of the use of various compounds within one strategy is very important. The most desirable are combinations of drugs that inhibit different steps in the virus life cycle. This is an important issue especially for RNA viruses, which replicate their genomes using error-prone RNA polymerases and rapidly develop mutants resistant to applied antiviral compounds. Here, we focus on compounds targeting viral structural capsid proteins, thereby inhibiting virus assembly or disassembly, virus binding to cellular receptors, or acting by inhibiting other virus replication mechanisms. This review is an update of existing papers on a similar topic, by focusing on the most recent advances in the rapidly evolving research of compounds targeting capsid proteins of RNA viruses.

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“…It has therefore been inferred that the FIV core had similar assembly constraints, and that its formation is likely to involve pentamers and hexamers of FIV CA. However, the structures of these FIV oligomers have yet to be identified [42].…”

Section: Fiv Camentioning

confidence: 99%

“…Interestingly, GS-6207 binds at the CA/CA interface within HIV-1 CA hexamers and has been optimized from lead molecules using the structural data available on these hexamers [14,52,53]. For FIV, assembly inhibitors have recently been identified that bind the same region of CA, which seems to be similarly able to interact with feline nucleoporins [42,54] and thus represent an interesting therapeutic target. Obtaining structural data on FIV CA oligomers will therefore be of prime importance for the optimization of these compounds towards efficient anti-FIV molecules.…”

Section: Fiv Camentioning

confidence: 99%

Review and Perspectives on the Structure–Function Relationships of the Gag Subunits of Feline Immunodeficiency Virus

2021

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The Gag polyprotein is implied in the budding as well as the establishment of the supramolecular architecture of infectious retroviral particles. It is also involved in the early phases of the replication of retroviruses by protecting and transporting the viral genome towards the nucleus of the infected cell until its integration in the host genome. Therefore, understanding the structure–function relationships of the Gag subunits is crucial as each of them can represent a therapeutic target. Though the field has been explored for some time in the area of Human Immunodeficiency Virus (HIV), it is only in the last decade that structural data on Feline Immunodeficiency Virus (FIV) Gag subunits have emerged. As FIV is an important veterinary issue, both in domestic cats and endangered feline species, such data are of prime importance for the development of anti-FIV molecules targeting Gag. This review will focus on the recent advances and perspectives on the structure–function relationships of each subunit of the FIV Gag polyprotein.

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Identification of a Potential Inhibitor of the FIV p24 Capsid Protein and Characterization of Its Binding Site

Abstract: RID-AGE-Risk factors and molecular determinants of aging-related,

Cited by 4 publications

References 73 publications

Identification of 2-(4-N,N-Dimethylaminophenyl)-5-methyl-1-phenethyl-1H-benzimidazole targeting HIV-1 CA capsid protein and inhibiting HIV-1 replication in cellulo

Identification of 2-(4-N,N-Dimethylaminophenyl)-5-methyl-1-phenethyl-1H-benzimidazole targeting HIV-1 CA capsid protein and inhibiting HIV-1 replication in cellulo

Targeting the Virus Capsid as a Tool to Fight RNA Viruses

Review and Perspectives on the Structure–Function Relationships of the Gag Subunits of Feline Immunodeficiency Virus

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