Orally Bioavailable RORγ/DHODH Dual Host-Targeting Small Molecules with Broad-Spectrum Antiviral Activity

Antiviral Research, Journal Year: 2024, Volume and Issue: unknown, P. 106008 - 106008

Published: Sept. 1, 2024

Language: Английский

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RORγt inhibitors in clinical development for the treatment of autoimmune diseases: challenges and opportunities

Expert Opinion on Therapeutic Patents, Journal Year: 2025, Volume and Issue: unknown

Published: March 20, 2025

Nuclear receptor retinoid-related orphan gamma-t (RORγt) is a major transcription factor for Th17 cell differentiation and IL-17 production. RORγt has been considered as promising drug target the treatment of IL-17-mediated inflammatory diseases. Numerous small molecule inhibitors have discovered, more than twenty advanced to clinical trials. However, none these compounds yet achieved market approval. This manuscript summarizes development 22 clinical-stage inhibitors, including their structures, patent applications, trial status, based on publications patents available up November 2024. The discovery was an exciting field molecular treatments, which gone through boom period in past ten years. some leading recently failed trials due lack efficacy or having safety concerns, although few candidates targeting are still preclinical studies. Realizing challenge, researchers started develop different approaches such dual exploring new indications, utilizing potential value inhibitors.

Language: Английский

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Cyclin-Dependent Kinase 8 Represents a Positive Regulator of Cytomegalovirus Replication and a Novel Host Target for Antiviral Strategies

Pharmaceutics, Journal Year: 2024, Volume and Issue: 16(9), P. 1238 - 1238

Published: Sept. 23, 2024

Background. Cyclin-dependent kinase 8 (CDK8) is a multifaceted regulator and represents catalytic component of the transcriptional Mediator complex. CDK8 activity, on one hand, increases elongation by recruitment Mediator/super complexes, but, other negatively regulates CDK7-controlled initiation through inactivating cyclin H phosphorylation. Recently, these combined properties have also suggested its rate-limiting importance for herpesviral replication. Objectives. In this paper, we focused human cytomegalovirus (HCMV) addressed question whether pharmacological inhibition or knock-down may affect viral replication efficiency in cell culture models. Methods. A number animal herpesviruses, as well non-herpesviruses, were used to analyze models, assess antiviral efficacy inhibitors. Results. Using clinically relevant inhibitors (CCT-251921, MSC-2530818, BI-1347), HCMV was found strongly reduced even at nanomolar drug concentrations. The EC50 values consistent three different strains (i.e., AD169, TB40, Merlin) analyzed two types primary fibroblasts astrocytoma cells), drugs comprised low level cytotoxicity. findings highlighted following: (i) pronounced vitro SI anti-HCMV activity obtained with inhibitors; (ii) confirmation CDK8–siRNA knock-down; (iii) CDK8-dependent reduction immediate early, late protein levels; (iv) main late-stage replication; (v) several mechanistic aspects, which point strong impact progeny production release, but lack relevance entry nuclear egress; (vi) significant synergy combinations against host vCDK/pUL97 (maribavir); (vii) finally, broad-spectrum seen comparison selected α-, β-, γ-, non-herpesviruses. Conclusions. summary, novel data provide evidence positive efficiency, moreover, suggest exploitability an target strategies host-directed development.

Language: Английский

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Discovery of 1-(Phenylsulfonyl)-1,2,3,4-tetrahydroquinoline Derivative as Orally Bioavailable and Safe RORγt Inverse Agonists for Potential Treatment of Rheumatoid Arthritis

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(22), P. 20315 - 20342

Published: Nov. 15, 2024

The retinoic acid receptor-related orphan receptor γt (RORγt) is a key regulator of Th17 cells, associated with autoimmune diseases, making it significant drug target. Herein, we designed and synthesized 1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline derivatives, improving upon GSK2981278 to enhance bioavailability. Of which,

Language: Английский

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Facile Synthesis of New Antiviral Fluoro-Quinazolines Enabled by Merging Domino Reactions

Synthesis, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 12, 2024

Abstract Quinazolines, particularly fluoro-quinazolines, represent important structural motifs in bioactive molecules and pharmaceuticals. Despite several known synthetic routes, the efficient synthesis of fluorine-containing quinazolines remains a challenge. Herein, straightforward sustainable fluorine-substituted using domino sequences is reported. The obtained novel fluoro-quinazoline compounds exhibit significant vitro activity against human cytomegalovirus (HCMV), expanding library potential antiviral drug compounds. Our finding outlays toolkit for fluoro-quinazolines introduces new agents HCMV therapy.

Language: Английский

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