Medicinal chemistry strategies toward host targeting antiviral agents

Ji, Xingyue; Li, Zhuorong

doi:10.1002/med.21664

Cited by 84 publications

(84 citation statements)

References 247 publications

(259 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Importantly, the exact target and mechanism of action of this compound remain to be determined; however, the data from virologic, resistance, and imaging studies presented here raise the intriguing possibility that this compound does not specifically target a viral protein, but instead may target a host component of a multi-protein complex that plays an important role in assembly of the immature HIV-1 capsid. While further studies will be needed to test this hypothesis, PAV206 and its analogs should be of great interest even at this early stage given that all existing antiretroviral drugs except one (CCR5 antagonists) target viral proteins (direct-acting antivirals) and that host-targeting antivirals are highly desirable because they offer a high genetic barrier to resistance that could allow us to win the drug resistance race (46, 47).…”

Section: Discussionmentioning

confidence: 99%

Identification of an antiretroviral small molecule that appears to be a host-targeting inhibitor of HIV-1 assembly

Reed

Solas²,

Kitaygorodskyy³

et al. 2020

Preprint

View full text Add to dashboard Cite

Given the projected increase in multidrug resistant HIV-1, there is an urgent need for development of antiretrovirals that act on virus life-cycle stages that are not targeted by antiretrovirals currently in use. Host-targeting drugs are of particular interest because they can offer a high barrier to resistance. Here we report identification of two related small molecules that inhibit HIV-1 late events, a stage of the HIV-1 life cycle for which potent and specific inhibitors are lacking. This chemotype was discovered using cell-free protein synthesis and assembly systems that recapitulate intracellular host-catalyzed viral capsid assembly pathways. These compounds inhibit replication of HIV-1 in human T cell lines and PBMCs and are effective against a primary isolate. They reduce virus production, likely by inhibiting a post-translational step in HIV-1 Gag assembly. Notably, the compound colocalizes with HIV-1 Gag in situ; however, unexpectedly, selection experiments failed to identify compound-specific resistance mutations in gag or pol, even though known resistance mutations developed in a parallel nelfinavir selection. Thus, we hypothesized that instead of binding to Gag directly, these compounds might localize to assembly intermediates, the intracellular multiprotein complexes containing Gag and host factors that are formed during immature HIV-1 capsid assembly. Indeed, imaging of infected cells showed colocalization of the compound with two host enzymes found in assembly intermediates, ABCE1 and DDX6. While the exact target and mechanism of action of this chemotype remain to be determined, these findings suggest that these compounds represent first-in-class, host-targeting inhibitors of intracellular events in HIV-1 assembly.IMPORTANCEThe success of antiretroviral treatment for HIV-1 is at risk of being undermined by the growing problem of drug resistance. Thus, there is a need to identify antiretrovirals that act on viral life cycle stages not targeted by drugs in use, such as the events of HIV-1 Gag assembly. To address this gap, we developed a compound screen that recapitulates the intracellular events of HIV-1 assembly, including viral-host interactions that promote assembly. This effort led to identification of a new chemotype that inhibits HIV-1 replication at nanomolar concentrations by inhibiting virus production. This compound colocalized with Gag and two host enzymes that facilitate capsid assembly but resistance selection did not result in compound-specific mutations in gag, suggesting that the chemotype does not directly target Gag. We hypothesize that this chemotype may represent a first-in-class inhibitor of virus production that acts by targeting a viral-host complex important for HIV-1 Gag assembly.

show abstract

Section: Discussionmentioning

confidence: 99%

Identification of an antiretroviral small molecule that appears to be a host-targeting inhibitor of HIV-1 assembly

Reed

Solas²,

Kitaygorodskyy³

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…On the other hand, proteins of different species or even genotypes of virus not often share structural similarity, as well as the ability of viruses to mutate during replication cause that the antiviral drug which targets a specific viral protein is not always effective against another virus. Noteworthy, there is a lack of effective antiviral drugs on the market ( Ji and Li, 2020 ). The extremely high mutation rates of RNA viruses may lead to drug resistance induction and circumvent vaccine-induced immunity ( Dinesh et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Antiviral activity of chlorpromazine, fluphenazine, perphenazine, prochlorperazine, and thioridazine towards RNA-viruses. A review

Otręba

Kośmider

Rzepecka‐Stojko

2020

European Journal of Pharmacology

View full text Add to dashboard Cite

In 2020 the whole world focused on antivirus drugs towards SARS-CoV-2. Most of the researchers focused on drugs used in other viral infections or malaria. We have not seen such mobilization towards one topic in this century. The whole situation makes clear that progress needs to be made in antiviral drug development. The first step to do it is to characterize the potential antiviral activity of new or already existed drugs on the market. Phenothiazines are antipsychotic agents used previously as antiseptics, anthelminthics, and antimalarials. Up to date, they are tested for a number of other disorders including the broad spectrum of viruses. The goal of this paper was to summarize the current literature on activity toward RNA-viruses of such drugs like chlorpromazine, fluphenazine, perphenazine, prochlorperazine, and thioridazine. We identified 49 papers, where the use of the phenothiazines for 23 viruses from different families were tested. Chlorpromazine, fluphenazine, perphenazine, prochlorperazine, and thioridazine possess anti-viral activity towards different types of viruses. These drugs inhibit clathrin-dependent endocytosis, cell-cell fusion, infection, replication of the virus, decrease viral invasion as well as suppress entry into the host cells. Additionally, since the drugs display activity at nontoxic concentrations they have therapeutic potential for some viruses, still, further research on animal and human subjects are needed in this field to verify cell base research.

show abstract

“…According to the WHO, due to its safety and medicinal capacity, most countries rely on herbal products 32 Therefore, viral replication can be blocked using the host protein inhibitor. The host protein inhibitor will be antiviral drug 35 . Several drugs are predicted to be used in the treatment of COVID-19 but still debated 36 .…”

Section: Discussionmentioning

confidence: 99%

In Silico Approach of Potential Phytochemical Inhibitor from Moringa oleifera, Cocos nucifera, Allium cepa, Psidium guajava, and Eucalyptus globulus for the treatment of COVID-19 by Molecular Docking

Fitriani

Utami²,

Zikri

et al. 2020

Preprint

View full text Add to dashboard Cite

Background Coronavirus disease 2019 (COVID-19) is caused by infection with severe acute respiratory syndrome coronavirus 2. COVID-19 has devastating effects on people in all countries and getting worse. We aim to investigate an in-silico docking analysis of phytochemical compounds from medicinal plants that used to combat inhibition of the COVID-19 pathway. There are several phytochemicals in medicinal plants, however, the mechanism of bioactive compounds remains unclear. These results are obtained from in silico research provide further information to support the inhibition of several phytochemicals. Methods Molecular docking used to determine the best potential COVID-19 M pro inhibitor from several bioactive compounds in Moringa oleifera, Allium cepa, Cocos nucifera, Psidium guajava, and Eucalyptus globulus. Molecular docking was conducted and scored by comparison with standard drugs remdesivir. ADME properties of selected ligands were evaluated using the Lipinski Rule. The interaction mechanism of the most recommended compound predicted using the STITCH database. Results There was no recommended compound in Moringa oleifera as a potential inhibitor for COVID-19. Oleanolic acid in Allium cepa, α-tocotrienol in Cocos nucifera, asiatic acid in Psidium guajava and culinoside in Eucalyptus globulus were the most recommended compound in each medicinal plant. Oleanolic acid was reported to exhibit anti-COVID-19 activity with binding energy was − 9.20 kcal/mol. This score was better than remdesivir as standard drug. Oleanolic acid interacted through the hydrogen bond with HIS41, THR25, CYS44, GLU166. Oleanolic acid binding with CASP-3, CASP-9, and XIAP signaling pathway. Conclusions Oleanolic acid in Allium cepa found as a potential inhibitor of COVID-19 M-pro that should be examined in future studies. These results suggest that oleanolic acid may be useful in COVID-19 treatment.

show abstract

Medicinal chemistry strategies toward host targeting antiviral agents

Cited by 84 publications

References 247 publications

Identification of an antiretroviral small molecule that appears to be a host-targeting inhibitor of HIV-1 assembly

Identification of an antiretroviral small molecule that appears to be a host-targeting inhibitor of HIV-1 assembly

Antiviral activity of chlorpromazine, fluphenazine, perphenazine, prochlorperazine, and thioridazine towards RNA-viruses. A review

In Silico Approach of Potential Phytochemical Inhibitor from Moringa oleifera, Cocos nucifera, Allium cepa, Psidium guajava, and Eucalyptus globulus for the treatment of COVID-19 by Molecular Docking

Contact Info

Product

Resources

About