Author: Smith, Stephanie A. ; Spears, Grant M. ; Zietlow, John ; Park, Myung S. ; Kozar, Rosemary A. ; Bailey, Kent R. ; Yudin, Nikoli ; Kizhakkedathu, Jayachandran N. ; La, Chanel C. ; Navarro, Sergio M. ; Goswami, Julie ; Dong, Jing-Fei ; Morrissey, James H. ; Vappala, Sreeparna ; MacArthur, Taleen A.

ABSTRACTBackground: Inorganic polyphosphate (polyP) is a procoagulant polyanion. We assessed the impact of polyP inhibition on thrombin generation after trauma using the novel polyP antagonists, macromolecular polyanion inhibitor 8 (MPI 8), and universal heparin reversal agent 8 (UHRA-8). Methods: Plasma thrombin generation (calibrated automated thrombogram, CAT), in 56 trauma patients and 39 controls +/− MPI 8 and UHRA-8 (50 μg/mL), was expressed as lag time (LT, minutes), peak height (PH, nM), and time to peak (ttPeak, minutes), with change in LT (ΔLT) and change in ttPeak (ΔttPeak) quantified. Results expressed in median and quartiles [Q1, Q3], Wilcoxon matched-pairs testing, P < 0.05 significant. Results: Trauma patients had greater baseline PH than controls (182.9 [121.0, 255.2]; 120.5 [62.1, 174.8], P < 0.001). MPI 8 treatment prolonged LT and ttPeak in trauma (7.20 [5.88, 8.75]; 6.46 [5.45, 8.93], P = 0.020; 11.28 [8.96, 13.14]; 11.00 [8.95, 12.94], P = 0.029) and controls (7.67 [6.67, 10.50]; 6.33 [5.33, 8.00], P < 0.001; 13.33 [11.67, 15.33]; 11.67 [10.33, 13.33], P < 0.001). UHRA-8 treatment prolonged LT and ttPeak and decreased PH in trauma (9.09 [7.45, 11.33]; 6.46 [5.45, 8.93]; 14.02 [11.78, 17.08]; 11.00 [8.95, 12.94]; 117.4 [74.5, 178.6]; 182.9 [121.0, 255.2]) and controls (9.83 [8.00, 12.33]; 6.33 [5.33, 8.00]; 16.67 [14.33, 20.00]; 11.67 [10.33, 13.33]; 55.3 [30.2, 95.9]; 120.5 [62.1, 174.8]), all P < 0.001. Inhibitor effects were greater for controls (greater ΔLT and ΔttPeak for both inhibitors, P < 0.001). Conclusion: PolyP inhibition attenuates thrombin generation, though to a lesser degree in trauma than in controls, suggesting that polyP contributes to accelerated thrombin generation after trauma.

29 Sep 2023·bioRxiv : the preprint server for biology

Discovery of First-in-Class PROTAC Degraders of SARS-CoV-2 Main Protease.

Author: Liu, Wenshe Ray ; Khatua, Kaustav ; Neuman, Benjamin W ; Ma, Xinyu R ; Xu, Shiqing ; Blankenship, Lauren ; Coleman, Demonta ; Xiao, Jing ; Ma, Yuying ; Vulupala, Veerabhadra R ; Kumar, Sathish ; Alugubelli, Yugendar R ; Atla, Sandeep R

We have witnessed three coronavirus (CoV) outbreaks in the past two decades, including the COVID-19 pandemic caused by SARS-CoV-2. Main protease (M ^Pro ) is a highly conserved and essential protease that plays key roles in viral replication and pathogenesis among various CoVs, representing one of the most attractive drug targets for antiviral drug development. Traditional antiviral drug development strategies focus on the pursuit of high-affinity binding inhibitors against M ^Pro . However, this approach often suffers from issues such as toxicity, drug resistance, and a lack of broad-spectrum efficacy. Targeted protein degradation represents a promising strategy for developing next-generation antiviral drugs to combat infectious diseases. Here we leverage the proteolysis targeting chimera (PROTAC) technology to develop a new class of small-molecule antivirals that induce the degradation of SARS-CoV-2 M ^Pro . Our previously developed M ^Pro inhibitors MPI8 and MPI29 were used as M ^Pro ligands to conjugate a CRBN E3 ligand, leading to compounds that can both inhibit and degrade SARS-CoV-2 M ^Pro . Among them, MDP2 was demonstrated to effectively reduce M ^Pro protein levels in 293T cells (DC ₅₀ = 296 nM), relying on a time-dependent, CRBN-mediated, and proteasome-driven mechanism. Furthermore, MPD2 exhibited remarkable efficacy in diminishing M ^Pro protein levels in SARS-CoV-2-infected A549-ACE2 cells, concurrently demonstrating potent anti-SARS-CoV-2 activity (EC ₅₀ = 492 nM). This proof-of-concept study highlights the potential of PROTAC-mediated targeted protein degradation of M ^Pro as an innovative and promising approach for COVID-19 drug discovery.

23 Feb 2022·ACS Central ScienceQ1 · CHEMISTRY

Evaluation of SARS-CoV-2 Main Protease Inhibitors Using a Novel Cell-Based Assay

Q1 · CHEMISTRY

ArticleOA

Author: Shaabani, Namir ; Ma, Xinyu R. ; Allen, Robert ; Ellenburg, William H. ; Geng, Zhi Zachary ; Neuman, Benjamin W. ; Alugubelli, Yugendar R. ; Ji, Henry ; Cho, Chia-Chuan Dean ; Xu, Shiqing ; Liu, Wenshe Ray ; Chaki, Sankar P. ; Ma, Yuying ; Vatansever, Erol C. ; Yang, Kai S. ; Qiao, Yuchen ; Cao, Wenyue

As an essential enzyme of SARS-CoV-2, main protease (M^Pro) triggers acute toxicity to its human cell host, an effect that can be alleviated by an M^Pro inhibitor. Using this toxicity alleviation, we developed an effective method that allows a bulk analysis of the cellular potency of M^Pro inhibitors. This novel assay is advantageous over an antiviral assay in providing precise cellular M^Pro inhibition information to assess an M^Pro inhibitor. We used this assay to analyze 30 known M^Pro inhibitors. Contrary to their strong antiviral effects and up to 10 μM, 11a, calpain inhibitor II, calpain XII, ebselen, bepridil, chloroquine, and hydroxychloroquine showed relatively weak to undetectable cellular M^Pro inhibition potency implicating their roles in interfering with key steps other than just the M^Pro catalysis in the SARS-CoV-2 life cycle. Our results also revealed that MPI5, MPI6, MPI7, and MPI8 have high cellular and antiviral potency. As the one with the highest cellular and antiviral potency among all tested compounds, MPI8 has a remarkable cellular M^Pro inhibition IC₅₀ value of 31 nM that matches closely to its strong antiviral effect with an EC₅₀ value of 30 nM. Therefore, we cautiously suggest exploring MPI8 further for COVID-19 preclinical tests.

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