Alphavirus capsid protease inhibitors as potential antiviral agents for Chikungunya infection

Fatma, Benazir; Kumar, Ravi; Singh, Vedita Anand; Nehul, Sanketkumar; Sharma, Rajesh; Kesari, Pooja; Kühn, Richard; Tomar, Shailly

doi:10.1016/j.antiviral.2020.104808

Cited by 32 publications

(21 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…GR hydrochloride is an antagonist of 5-HT1B/1D serotonin receptor, and also plays a role in inhibiting entry of Ebola virus entry into host cell (49). Eptifibatide acetate protects lungs from inflammations caused by influenza virus, and has been reported as antiviral that inhibits the protease activity of Chikungunya virus capsid protein (50,51). KT185 and KT203, inhibitors of S-RBD protein of SARS-CoV-2 are known to exert anti-inflammatory role on lungs (52,53).…”

Section: Discussionmentioning

confidence: 99%

Identification of SARS-CoV-2 Cell Entry Inhibitors by Drug Repurposing Using in silico Structure-Based Virtual Screening Approach

2020

Self Cite

View full text Add to dashboard Cite

The rapidly spreading, highly contagious and pathogenic SARS-coronavirus 2 (SARS-CoV-2) associated Coronavirus Disease 2019 (COVID-19) has been declared as a pandemic by the World Health Organization (WHO). The novel 2019 SARS-CoV-2 enters the host cell by binding of the viral surface spike glycoprotein (S-protein) to cellular angiotensin converting enzyme 2 (ACE2) receptor. The virus specific molecular interaction with the host cell represents a promising therapeutic target for identifying SARS-CoV-2 antiviral drugs. The repurposing of drugs can provide a rapid and potential cure toward exponentially expanding COVID-19. Thereto, high throughput virtual screening approach was used to investigate FDA approved LOPAC library drugs against both the receptor binding domain of spike protein (S-RBD) and ACE2 host cell receptor. Primary screening identified a few promising molecules for both the targets, which were further analyzed in details by their binding energy, binding modes through molecular docking, dynamics and simulations. Evidently, GR 127935 hydrochloride hydrate, GNF-5, RS504393, TNP, and eptifibatide acetate were found binding to virus binding motifs of ACE2 receptor. Additionally, KT203, BMS195614, KT185, RS504393, and GSK1838705A were identified to bind at the receptor binding site on the viral S-protein. These identified molecules may effectively assist in controlling the rapid spread of SARS-CoV-2 by not only potentially inhibiting the virus at entry step but are also hypothesized to act as anti-inflammatory agents, which could impart relief in lung inflammation. Timely identification and determination of an effective drug to combat and tranquilize the COVID-19 global crisis is the utmost need of hour. Further, prompt in vivo testing to validate the anti-SARS-CoV-2 inhibition efficiency by these molecules could save lives is justified.

show abstract

Section: Discussionmentioning

confidence: 99%

Identification of SARS-CoV-2 Cell Entry Inhibitors by Drug Repurposing Using in silico Structure-Based Virtual Screening Approach

2020

Self Cite

View full text Add to dashboard Cite

show abstract

“…These compounds showed half-maximal effective concentrations (EC 50 ) of 4.01 mM, 10.66 mM, and 22.91 mM, respectively. This report was the first to demonstrate that alphavirus CP protease could be successfully blocked by inhibitors opening a way for the development of novel antiviral drugs (Fatma et al 2020).…”

Section: Alphavirus Proteasementioning

confidence: 91%

Viral Proteases

Skoreński

Grzywa

Sieńczyk

2021

Encyclopedia of Molecular Pharmacology

View full text Add to dashboard Cite

show abstract

“…The cysteine protease activity of the alphavirus nsP2 is located in its C-terminal region and is needed for processing of the nonstructural viral polyprotein [ 31 ]. On the other hand, the C-terminal part of the capsid protein (CP) possesses a serine auto-protease activity, which is essential for its release from the structural polyprotein [ 32 ].…”

Section: Antiviral Strategiesmentioning

confidence: 99%

“…In contrast to the multiple studies targeting the nsP2 protease, studies exploring the capsid protease are scarce. The first study confirming that the alphavirus CP protease could be a potential druggable target was published very recently [ 32 ]. Three inhibitors of CHIKV CP autoprotease activity (i.e., EAC ( Figure 2 ), AP4, and PSU) were identified by structure-based virtual screening of the LOPAC ® compounds library (Sigma Aldrich) against the crystal structure of CHIKV CP protease [ 32 ].…”

Section: Antiviral Strategiesmentioning

confidence: 99%

“…The first study confirming that the alphavirus CP protease could be a potential druggable target was published very recently [ 32 ]. Three inhibitors of CHIKV CP autoprotease activity (i.e., EAC ( Figure 2 ), AP4, and PSU) were identified by structure-based virtual screening of the LOPAC ® compounds library (Sigma Aldrich) against the crystal structure of CHIKV CP protease [ 32 ]. The anti-CP proteolytic activity of these compounds were confirmed in a FRET-based proteolytic assay and they also proved to inhibit CHIKV replication in Vero cells [ 32 ].…”

Section: Antiviral Strategiesmentioning

confidence: 99%

See 1 more Smart Citation

Antiviral Strategies against Arthritogenic Alphaviruses

Abdelnabi

2020

Microorganisms

View full text Add to dashboard Cite

Alphaviruses are members of the Togaviridae family that are mainly transmitted by arthropods such as mosquitoes. In the last decades, several alphaviruses have re-emerged, causing outbreaks worldwide. One example is the re-emergence of chikungunya virus (CHIKV) in 2004, which caused massive epidemics in the Indian Ocean region after which the virus dramatically spread to the Americas in late 2013. Besides CHIKV, other alphaviruses, such as the Ross River virus (RRV), Mayaro virus (MAYV), and Venezuelan equine encephalitis virus (VEEV), have emerged and have become a serious public health concern in recent years. Infections with the Old World alphaviruses (e.g., CHIKV, RRV) are primarily associated with polyarthritis and myalgia that can persist for months to years. On the other hand, New World alphaviruses such as VEEV cause mainly neurological disease. Despite the worldwide (re-)emergence of these viruses, there are no antivirals or vaccines available for the treatment or prevention of infections with alphaviruses. It is therefore of utmost importance to develop antiviral strategies against these viruses. We here provided an overview of the reported antiviral strategies against arthritogenic alphaviruses. In addition, we highlighted the future perspectives for the development and the proper use of such antivirals.

show abstract

Alphavirus capsid protease inhibitors as potential antiviral agents for Chikungunya infection

Cited by 32 publications

References 46 publications

Identification of SARS-CoV-2 Cell Entry Inhibitors by Drug Repurposing Using in silico Structure-Based Virtual Screening Approach

Identification of SARS-CoV-2 Cell Entry Inhibitors by Drug Repurposing Using in silico Structure-Based Virtual Screening Approach

Viral Proteases

Antiviral Strategies against Arthritogenic Alphaviruses

Contact Info

Product

Resources

About