Small Molecules Targeting the Flavivirus E Protein with Broad-Spectrum Activity and Antiviral Efficacy <i>in Vivo</i>

Targeted protein degradation is a promising drug development paradigm. Here we leverage this strategy to develop a new class of small molecule antivirals that induce proteasomal degradation of viral proteins. Telaprevir, a reversible-covalent inhibitor that binds to the hepatitis C virus (HCV) protease active site is conjugated to ligands that recruit the CRL4 CRBN ligase complex, yielding compounds that can both inhibit and induce the degradation of the HCV NS3/4A protease. An optimized degrader, DGY-08-097, potently inhibits HCV in a cellular infection model, and we demonstrate that protein degradation contributes to its antiviral activity. Finally, we show that this new class of antiviral agents can overcome viral variants that confer resistance to traditional enzymatic inhibitors such as telaprevir. Overall, our work provides proof-of-concept that targeted protein degradation may provide a new paradigm for the development of antivirals with superior resistance profiles.

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“…7). 3-110-22, a compound previously shown to exhibit non-specific MDH inhibition 49 , was used as a positive control.…”

Section: Methodsmentioning

confidence: 99%

Small molecule degraders of the hepatitis C virus protease reduce susceptibility to resistance mutations

et al. 2019

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“…Compound 29 showed poor stability in mouse microsomes (T 1 / 2 = 13 min) and toxicity in mice, thus, a series of analogues with different substituents at ortho/meta positions of the phenyl ring with respect to the trifluoromethyl group was synthesized. [127] Compound 30 showed comparable anti-DENV-2 and cytotoxic profiles to 29 and a slight improvement of the metabolic stability, that was still low (T 1 / 2 = 64.8 min) (Figure 8). However, in vivo activity (2-daily 40 mg/kg i. p.) in DENV-2 infected-AG129 mice was moderate, likely due to still low metabolic stability and a high level of plasma-protein binding (> 99.9 %).…”

Section: E Protein Inhibitorsmentioning

confidence: 94%

Broad‐Spectrum Flavivirus Inhibitors: a Medicinal Chemistry Point of View

et al. 2020

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Infections by flaviviruses, such as Dengue, West Nile, Yellow Fever and Zika viruses, represent a growing risk for global health. There are vaccines only for few flaviviruses while no effective treatments are available. Flaviviruses share epidemiological, structural, and ecologic features and often different viruses can co‐infect the same host. Therefore, the identification of broad‐spectrum inhibitors is highly desirable either for known flaviviruses or for viruses that likely will emerge in the future. Strategies targeting both virus and host factors have been pursued to identify broad‐spectrum antiflaviviral agents. In this review, we describe the most promising and best characterized targets and their relative broad‐spectrum inhibitors, identified by drug repurposing/libraries screenings and by focused medicinal chemistry campaigns. Finally, we discuss about future strategies to identify new broad‐spectrum antiflavivirus agents.

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“…The nearby loop (ki) controls pocket deformation by movement, where the opening of the pocket can bind the β-OG region, and the ki loop and ij loop near the hydrophobic region form a salt bridge and hydrogen bond to assist the migration of the DII fusion peptide to the host membrane and promote fusion. Therefore, designing a small molecule that can combine with the pocket to form more hydrogen bonds may cause a conformational change of E protein before it reaches the Golgi apparatus [ 128 ], thus destroying the synthesis of virus particles and E-mediated membrane fusion, for example, cyanohydrazones inhibit 3-110-22 and JBJ-01-162-04 [ 129 ]. Prior to flavivirus particles reaching the Golgi body, prM and E proteins are cleaved by furin protease in host cells, and the virus particles mature.…”

Section: Structure-based Anti-flavivirus Drug Targetsmentioning

confidence: 99%

Flavivirus: From Structure to Therapeutics Development

Zhao

Wang

Cao

et al. 2021

Life

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Flaviviruses are still a hidden threat to global human safety, as we are reminded by recent reports of dengue virus infections in Singapore and African-lineage-like Zika virus infections in Brazil. Therapeutic drugs or vaccines for flavivirus infections are in urgent need but are not well developed. The Flaviviridae family comprises a large group of enveloped viruses with a single-strand RNA genome of positive polarity. The genome of flavivirus encodes ten proteins, and each of them plays a different and important role in viral infection. In this review, we briefly summarized the major information of flavivirus and further introduced some strategies for the design and development of vaccines and anti-flavivirus compound drugs based on the structure of the viral proteins. There is no doubt that in the past few years, studies of antiviral drugs have achieved solid progress based on better understanding of the flavivirus biology. However, currently, there are no fully effective antiviral drugs or vaccines for most flaviviruses. We hope that this review may provide useful information for future development of anti-flavivirus drugs and vaccines.

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Small Molecules Targeting the Flavivirus E Protein with Broad-Spectrum Activity and Antiviral Efficacy in Vivo

Cited by 30 publications

References 56 publications

Small molecule degraders of the hepatitis C virus protease reduce susceptibility to resistance mutations

Small molecule degraders of the hepatitis C virus protease reduce susceptibility to resistance mutations

Broad‐Spectrum Flavivirus Inhibitors: a Medicinal Chemistry Point of View

Flavivirus: From Structure to Therapeutics Development

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