HSP90: a promising broad-spectrum antiviral drug target

Abstract

The emergence of antiviral drug-resistant mutants is the most important issue in current antiviral therapy. As obligate parasites, viruses require host factors for efficient replication. An ideal therapeutic target to prevent drug-resistance development is represented by host factors that are crucial for the viral life cycle. Recent studies have indicated that heat shock protein 90 (HSP90) is a crucial host factor that is required by many viruses for multiple phases of their life cycle including viral entry, nuclear import, transcription, and replication. In this review, we summarize the most recent advances regarding HSP90 function, mechanisms of action, and molecular pathways that are associated with viral infection, and provide a comprehensive understanding of the role of HSP90 in the immune response and exosome-mediated viral transmission. In addition, several HSP90 inhibitors have entered clinical trials for specific cancers that are associated with viral infection, which further implies a crucial role for HSP90 in the malignant transformation of virus-infected cells; as such, HSP90 inhibitors exhibit excellent therapeutic potential. Finally, we describe the challenge of developing HSP90 inhibitors as anti-viral drugs.

Inhibition of heat shock protein 90 suppresses Bombyx mori nucleopolyhedrovirus replication in B. mori

“…The molecular chaperone Hsp90 is essential for the integrity, folding and function of viral and cellular proteins involved in proliferation, survival, DNA damage and repair (Hartl and Hayer‐Hartl, ; Tamm et al ., ).Hsp90 plays a very important role in facilitating viral infection. On the one hand, viruses, as obligate parasites, require host factors for their efficient replication (Wang et al ., ). Hsp90 promotes viral infection in different stages of the viral life cycle by interactions with critical viral factors including capsid proteins, DNA polymerase, virus RNA complexes and nonstructural proteins (Kawashima et al ., ; Rathore et al ., ; Tsou et al ., ; Vashist et al ., ).…”

“…Influenza A virus neuraminidase protein interacts with Hsp90 to stabilize itself and enhance cell survival (Kumar et al ., 2019). In addition, through association with many host factors, such as cell division cycle protein 37 (cdc37), protein kinase B (Akt) and translocase of outer membrane 70 (Tom70), Hsp90 plays multiple roles in different viral infections including immune responses, apoptosis, cellular proliferation and exosome production (Wang et al ., ).…”

Inhibition of Hepatitis C Replication by Targeting the Molecular Chaperone Hsp90: Synthesis and Biological Evaluation of 4,5,6,7‐Tetrahydrobenzo[1,2‐d]thiazole Derivatives

“…[30] In light of this information,i ti sn otably encouraging that compounds 2 and 5 were well toleratedi n vitro compared to the reference Hsp90 inhibitor 17-DMAG. The main challenge constraining the clinicald evelopment of Hsp90 inhibitors is in vivo toxicity, which has led to the postponemento rt ermination of Hsp90 inhibitor-associated clinical trials.…”

“…[28] Hsp90 contributes to the maturation,f olding, and stability of severalp roteins required for HCV replication. [19,[30][31][32] To assess Hsp90 inhibition as ap otential mechanism of action, the binding of compounds to Hsp90 wase valuated by microscalet hermophoresis (MST), which enables determination of bindinga ffinity based on the movemento fp articles in am icroscopict emperature gradient. [19,[30][31][32] To assess Hsp90 inhibition as ap otential mechanism of action, the binding of compounds to Hsp90 wase valuated by microscalet hermophoresis (MST), which enables determination of bindinga ffinity based on the movemento fp articles in am icroscopict emperature gradient.…”

Synthesis, biological evaluation and molecular modeling of novel azaspiro dihydrotriazines as influenza virus inhibitors targeting the host factor dihydrofolate reductase (DHFR)

“…Analyzing the role of the substituent at N (1) position of the new dihydrotriazines, a phenyl ring (2e6, 8,9) provided again activity against influenza B, and in some cases, influenza A virus, whereas a 3-chlorobenzyl moiety or n-propyl or methoxyethyl chain abolished the activity. The only exception was derivative 20, which displayed an EC 50 of 3.0 mM against influenza B virus; this molecule combined a methoxyethyl substitution at N (1) with an ethylsulfonic group, such as decoration of spiropiperidine nitrogen.…”