Last update 01 Nov 2024

CTSL x SARS-CoV-2 Mpro

Last update 01 Nov 2024

Basic Info

Related Targets

CTSLSARS-CoV-2 Mpro

Drugs associated with CTSL x SARS-CoV-2 Mpro

MPI-8

Target

CTSL x SARS-CoV-2 Mpro

Mechanism

CTSL inhibitors [+1]

Active Org.

Texas A&M University

Originator Org.

Texas A&M University

Active Indication

COVID-19

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with CTSL x SARS-CoV-2 Mpro

100 Translational Medicine associated with CTSL x SARS-CoV-2 Mpro

0 Patents (Medical) associated with CTSL x SARS-CoV-2 Mpro

Literatures (Medical) associated with CTSL x SARS-CoV-2 Mpro

09 May 2024·ACS Medicinal Chemistry Letters

Identification of Dual Inhibitors Targeting Main Protease (M^pro) and Cathepsin L as Potential Anti-SARS-CoV-2 Agents

Article

Author: Cigala, Rosalia Maria ; Previti, Santo ; Zappala, Maria ; Muller-Ruttloff, Christin ; Natale, Benito ; Salisch, Florian ; Ziebuhr, John ; Irto, Anna ; Cosconati, Sandro ; Weldert, Annabelle C. ; Ettari, Roberta ; Schirmeister, Tanja ; Roggia, Michele ; Calcaterra, Elsa

In this structure-activity relationship (SAR) study, we report the development of dual inhibitors with antiviral properties targeting the SARS-CoV-2 main protease (M^pro) and human cathepsin L (hCatL). The novel molecules differ in the aliphatic amino acids at the P2 site and the fluorine position on the phenyl ring at the P3 site. The identified dual inhibitors showed K_i values within 1.61 and 10.72 μM against SARS-CoV-2 M^pro; meanwhile, K_i values ranging from 0.004 to 0.701 μM toward hCatL were observed. A great interdependency between the nature of the side chain at the P2 site and the position of the fluorine atom was found. Three dual-targeting inhibitors exhibited antiviral activity in the low micromolar range with CC₅₀ values >100 μM. Docking simulations were executed to gain a deeper understanding of the SAR profile. The findings herein collected should be taken into consideration for the future development of dual SARS-CoV-2 M^pro/hCatL inhibitors.

01 Jan 2024·Med

Olgotrelvir, a dual inhibitor of SARS-CoV-2 Mpro and cathepsin L, as a standalone antiviral oral intervention candidate for COVID-19

Article

Author: Shao, Jianping ; Wang, Chao ; Kotoi, Olivia ; Zhang, Yuren ; Shen, Wei ; Shu, Dan ; Lin, Zhenhao ; Xu, Lijun ; Bao, Yimei ; Xu, Wanhong ; Stegman, Karen ; Wang, Shanbo ; Teijaro, John ; Zhu, Zhenhong ; Zhang, Xiaoying ; Qian, Shengdian ; Liu, Jia ; Jin, Can ; Liu, Na ; Li, Tingting ; Argent, Christopher ; Chumakova, Ludmila ; Royal, Mike ; Allen, Robert ; Lin, Yuanlong ; Zhang, Can ; Hu, Yong ; Xu, Changxu ; Powers, Colin ; Kushnareva, Yulia ; Han, Qing ; Xu, Xiao ; Lu, Hongzhou ; Ji, Henry ; Yang, Haigang ; Brunswick, Mark ; Kerwin, Lisa ; Xie, Hui ; Mao, Long ; Shaabani, Namir ; Li, Yi

BACKGROUNDOral antiviral drugs with improved antiviral potency and safety are needed to address current challenges in clinical practice for treatment of COVID-19, including the risks of rebound, drug-drug interactions, and emerging resistance.METHODSOlgotrelvir (STI-1558) is designed as a next-generation antiviral targeting the SARS-CoV-2 main protease (M^pro), an essential enzyme for SARS-CoV-2 replication, and human cathepsin L (CTSL), a key enzyme for SARS-CoV-2 entry into host cells.FINDINGSOlgotrelvir is a highly bioavailable oral prodrug that is converted in plasma to its active form, AC1115. The dual mechanism of action of olgotrelvir and AC1115 was confirmed by enzyme activity inhibition assays and co-crystal structures of AC1115 with SARS-CoV-2 M^pro and human CTSL. AC1115 displayed antiviral activity by inhibiting replication of all tested SARS-CoV-2 variants in cell culture systems. Olgotrelvir also inhibited viral entry into cells using SARS-CoV-2 Spike-mediated pseudotypes by inhibition of host CTSL. In the K18-hACE2 transgenic mouse model of SARS-CoV-2-mediated disease, olgotrelvir significantly reduced the virus load in the lungs, prevented body weight loss, and reduced cytokine release and lung pathologies. Olgotrelvir demonstrated potent activity against the nirmatrelvir-resistant M^pro E166 mutants. Olgotrelvir showed enhanced oral bioavailability in animal models and in humans with significant plasma exposure without ritonavir. In phase I studies (ClinicalTrials.gov: NCT05364840 and NCT05523739), olgotrelvir demonstrated a favorable safety profile and antiviral activity.CONCLUSIONSOlgotrelvir is an oral inhibitor targeting M^pro and CTSL with high antiviral activity and plasma exposure and is a standalone treatment candidate for COVID-19.FUNDINGFunded by Sorrento Therapeutics.

22 Jan 2022·Journal of Biomolecular Structure and Dynamics

Potential protease inhibitors and their combinations to block SARS-CoV-2

Article

Author: Krishnamurthy, Anand ; Oommen, Oommen V. ; Sudhakaran, Perumana R. ; Nair, Achuthsankar S. ; Abhinand, Chandran S.

COVID-19, which has emerged recently as a pandemic viral infection caused by SARS-coronavirus 2 has spread rapidly around the world, creating a public health emergency. The current situation demands an effective therapeutic strategy to control the disease using drugs that are approved, or by inventing new ones. The present study examines the possible repurposing of existing anti-viral protease inhibitor drugs. For this, the structural features of the viral spike protein, the substrate for host cell protease and main protease of the available SARS CoV-2 isolates were established by comparing with related viruses for which antiviral drugs are effective. The results showed 97% sequence similarity among SARS and SARS-CoV-2 main protease and has same cleavage site positions and ACE2 receptor binding region as in the SARS-CoV spike protein. Though both are N-glycosylated, unlike SARS-CoV, human SARS-CoV-2 S-protein was O-glycosylated as well. Molecular docking studies were done to explore the role of FDA approved protease inhibitors to control SARS-CoV-2 replication. The results indicated that, Ritonavir has the highest potency to block SARS-CoV-2 main protease and human TMPRSS2, a host cell factor that aids viral infection. Other drugs such as Indinavir and Atazanavir also showed favourable binding with Cathepsin B/L that helped viral fusion with the host cell membrane. Further molecular dynamics simulation and MM-PBSA binding free energy calculations confirmed the stability of protein-drug complexes. These results suggest that protease inhibitors particularly Ritonavir, either alone or in combination with other drugs such as Atazanavir, have the potential to treat COVID 19.Communicated by Ramaswamy H. Sarma.

Analysis

Perform a panoramic analysis of this field.

view full example data

Chat with Hiro

Get started for free today!

Accelerate Strategic R&D decision making with Synapse, PatSnap’s AI-powered Connected Innovation Intelligence Platform Built for Life Sciences Professionals.

Start your data trial now!

Synapse data is also accessible to external entities via APIs or data packages. Empower better decisions with the latest in pharmaceutical intelligence.

Bio

Bio Sequences Search & Analysis

Chemical

Chemical Structures Search & Analysis