As the etiological agent for the coronavirus disease 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) challenges the ongoing efforts of vaccine development and drug design. Due to the accumulating cases of breakthrough infections, there are urgent needs for broad-spectrum antiviral medicines. Here, we designed and examined five new tetrapeptidomimetic anti-SARS-CoV-2 inhibitors targeting the 3C-Like protease (3CL), which is highly conserved among coronaviruses and essential for viral replications. We significantly improved the efficacy of a ketoamide lead compound based on high-resolution co-crystal structures, all-atom simulations, and binding energy calculations. The inhibitors successfully engaged the catalytic dyad histidine residue (H41) of 3CLPro as designed, and they exhibited nanomolar inhibitory capacity as well as mitigated the viral loads of SARS-CoV-2 in cellular assays. As a widely applicable design principle, our results revealed that the potencies of 3CL-specific drug candidates were determined by the interplay between 3CL H41 residue and the peptidomimetic inhibitors.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8878928 | PMC |
| http://dx.doi.org/10.3390/ijms23042392 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Design, Synthesis, and Biological Evaluation of 1,3,4-Thiadiazole Derivatives as Novel Potent Peptide Deformylase Inhibitors for Combating Drug-Resistant Gram-Positive and -Negative Bacteria.
J Med Chem
January 2025
Shanghai Applied Radiation Institute, School of Environmental and Chemical Engineering, Shanghai University, Shanghai 200444, P. R. China.
The prevalence of drug-resistant bacteria is a major challenge throughout the world, especially with respect to Gram-negative bacteria, such as drug-resistant , which are regarded as the greatest bacterial threat to human health by the World Health Organization (WHO). In this work, 1,3,4-thiadiazole was introduced into the main skeleton of the classical peptidomimetic peptide deformylase (PDF) inhibitor in pursuit of highly efficient and broad-spectrum bacteriostatic drugs. Upon detailed structure-activity relationship study, PDF inhibitors that possess satisfactory activity against both Gram-positive and Gram-negative bacteria as well as a lower potential for methemoglobin toxicity were screened out.
View Article and Find Full Text PDFDual Inhibitors of SARS-CoV-2 3CL Protease and Human Cathepsin L Containing Glutamine Isosteres Are Anti-CoV-2 Agents.
J Am Chem Soc
January 2025
Department of Biochemistry and Biophysics, Texas A&M University, 301 Old Main Drive, College Station, Texas 77845, United States.
SARS-CoV-2 3CL protease (Main protease) and human cathepsin L are proteases that play unique roles in the infection of human cells by SARS-CoV-2, the causative agent of COVID-19. Both proteases recognize leucine and other hydrophobic amino acids at the P position of a peptidomimetic inhibitor. At the P position, cathepsin L accepts many amino acid side chains, with a partial preference for phenylalanine, while 3CL-PR protease has a stringent specificity for glutamine or glutamine analogues.
View Article and Find Full Text PDFAntiviral Agents: Structural Basis of Action and Rational Design.
Subcell Biochem
December 2024
Department of Biomedical Sciences, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain.
During the last forty years, significant progress has been made in the development of novel antiviral drugs, mainly crystallizing in the establishment of potent antiretroviral therapies and the approval of drugs eradicating hepatitis C virus infection. Although major targets of antiviral intervention involve intracellular processes required for the synthesis of viral proteins and nucleic acids, a number of inhibitors blocking virus assembly, budding, maturation, entry, or uncoating act on virions or viral capsids. In this review, we focus on the drug discovery process while presenting the currently used methodologies to identify novel antiviral drugs by means of computer-based approaches.
View Article and Find Full Text PDFBeyond peptides: Unveiling the design strategies, structure activity correlations and protein-ligand interactions of small molecule inhibitors against PD-1/PD-L1.
Bioorg Chem
January 2025
Department of Pharmaceutical Chemistry, College of Pharmaceutical Sciences, Dayananda Sagar University (DSU), Bengaluru 560 111, Karnataka, India; Department of Pharmaceutical Chemistry, R R College of Pharmacy, Bengaluru 560 090, Karnataka, India. Electronic address:
The landscape of cancer treatment has been transformed by the emergence of immunotherapy, especially through the use of antibodies that target the PD-1/PD-L1 pathway. Recently, there has been a notable increase in interest surrounding immune checkpoint inhibitors for cancer therapy. While antibody-based approaches have drawbacks like high costs and prolonged activity, the approval of monoclonal antibodies such as pembrolizumab and nivolumab has paved the way for a range of alternative therapies, including peptides, peptidomimetics, and small-molecule inhibitors.
View Article and Find Full Text PDFMechanistic Insights Into Post-Translational α-Keto-β-Amino Acid Formation by a Radical S-Adenosyl Methionine Peptide Splicease.
Angew Chem Int Ed Engl
December 2024
Institute of Microbiology, Eidgenössische Technische Hochschule (ETH) Zürich, 8093, Zurich, Switzerland.
Radical S-adenosyl methionine enzymes catalyze a diverse repertoire of post-translational modifications in protein and peptide substrates. Among these, an exceptional and mechanistically obscure example is the installation of α-keto-β-amino acid residues by formal excision of a tyrosine-derived tyramine unit. The responsible spliceases are key maturases in a widespread family of natural products termed spliceotides that comprise potent protease inhibitors, with the installed β-residues being crucial for bioactivity.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!