Discovery of all-D-peptide inhibitors of SARS CoV 2 3C-like protease DOI Creative Commons
Raphael J. Eberle, Marc Sevenich, Ian Gering

et al.

Published: June 14, 2022

During the replication process of SARS-CoV-2 main protease virus (3-chymotrypsin-like (3CLpro)) plays a pivotal role and is essential for life cycle pathogen. Numerous studies have been conducted so far, which confirmed 3CLpro as an attractive drug target to combat COVID-19. We describe novel efficient next generation sequencing (NGS) supported phage display selection strategy identification set targeting peptide ligands that inhibit 3CL protease, in competitive or non-competetive mode, low µM range. From most L-peptides obtained from display, we designed all-D-peptides based on retro-inverso (ri) principle. They had IC50 values also range, combination even sub-micromolar The inhibition modes these D-ri peptides were same their respective L-peptide versions. Our results demonstrate interact with high-affinity thus reinforcing potential therapeutic agents. here described address limitations associated current inhibitors are promising lead compounds. Further optimization regarding pharmacokinetic properties will allow development more potent D-peptides be used prevention treatment

Language: Английский

D‐Peptide and D‐Protein Technology: Recent Advances, Challenges, and Opportunities** DOI Creative Commons
Alexander J. Lander, Yi Jin, Louis Y. P. Luk

et al.

ChemBioChem, Journal Year: 2022, Volume and Issue: 24(4)

Published: Oct. 24, 2022

Abstract Total chemical protein synthesis provides access to entire D‐protein enantiomers enabling unique applications in molecular biology, structural and bioactive compound discovery. Key enzymes involved the central dogma of biology have been prepared their D‐enantiomeric forms facilitating development mirror‐image life. Crystallization a racemic mixture L‐ high‐resolution X‐ray structures polypeptides. Additionally, D‐enantiomers drug targets can be used phage display allowing discovery non‐proteolytic D‐peptide ligands as lead candidates. This review discusses D‐proteins including synthetic challenges opportunities.

Language: Английский

Citations

44
Virtual Screening of Peptide Libraries: The Search for Peptide-Based Therapeutics Using Computational Tools DOI Open Access
Marian Vincenzi, Flavia Anna Mercurio, Marilisa Leone

et al.

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(3), P. 1798 - 1798

Published: Feb. 1, 2024

Over the last few decades, we have witnessed growing interest from both academic and industrial laboratories in peptides as possible therapeutics. Bioactive a high potential to treat various diseases with specificity biological safety. Compared small molecules, represent better candidates inhibitors (or general modulators) of key protein–protein interactions. In fact, undruggable proteins containing large smooth surfaces can be more easily targeted conformational plasticity peptides. The discovery bioactive peptides, working against disease-relevant protein targets, generally requires high-throughput screening libraries, silico approaches are highly exploited for their low-cost incidence efficiency. present review reports on challenges linked employment therapeutics describes computational approaches, mainly structure-based virtual (SBVS), support identification novel therapeutic implementations. Cutting-edge SBVS strategies reviewed along examples applications focused diverse classes (i.e., anticancer, antimicrobial/antiviral blocking amyloid fiber formation).

Language: Английский

Citations

15
On the origins of SARS-CoV-2 main protease inhibitors DOI
Yves L. Janin

RSC Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 15(1), P. 81 - 118

Published: Oct. 13, 2023

In order to address the world-wide health challenge caused by COVID-19 pandemic, 3CL protease/SARS-CoV-2 main protease (SARS-CoV-2-M

Language: Английский

Citations

17
Discovery of All-d-Peptide Inhibitors of SARS-CoV-2 3C-like Protease DOI Creative Commons
Raphael J. Eberle, Marc Sevenich, Ian Gering

et al.

ACS Chemical Biology, Journal Year: 2023, Volume and Issue: 18(2), P. 315 - 330

Published: Jan. 17, 2023

During the replication process of SARS-CoV-2, main protease virus [3-chymotrypsin-like (3CLpro)] plays a pivotal role and is essential for life cycle pathogen. Numerous studies have been conducted so far, which confirmed 3CLpro as an attractive drug target to combat COVID-19. We describe novel efficient next-generation sequencing (NGS) supported phage display selection strategy identification set SARS-CoV-2 targeting peptide ligands that inhibit 3CL protease, in competitive or noncompetitive mode, low μM range. From most l-peptides obtained from display, we designed all-d-peptides based on retro-inverso (ri) principle. They had IC50 values also range combination, even sub-micromolar Additionally, combination with Rutinprivir decreases 10-fold value inhibitor. The inhibition modes these d-ri peptides were same their respective l-peptide versions. Our results demonstrate interact high affinity thus reinforcing potential further development toward therapeutic agents. here described address limitations associated current inhibitors are promising lead compounds. Further optimization regarding pharmacokinetic properties will allow more potent d-peptides be used prevention treatment

Language: Английский

Citations

13
Mechanism of Protease Resistance of D-Amino Acid Residue Containing Cationic Antimicrobial Heptapeptides DOI

Tanumoy Sarkar,

Suvankar Ghosh, Pradeep Kumar Sundaravadivelu

et al.

ACS Infectious Diseases, Journal Year: 2024, Volume and Issue: 10(2), P. 562 - 581

Published: Jan. 31, 2024

Antimicrobial peptides (AMPs) have been an alternate promising class of therapeutics in combating global antibiotic resistance threat. However, the short half-life AMPs, owing to protease degradability, is one major bottlenecks its commercial success. In this study, we developed all-D-amino acid containing small cationic P4C and P5C, which are completely protease-resistant, noncytotoxic, nonhemolytic, potent against ESKAPE pathogens comparison their L analogues. MD simulations suggested marginal improvement peptide-binding affinity membrane-mimetic SDS micelle (∼ 1 kcal/mol) response → D conversion, corroborating antimicrobial activity. chirality conversion severely compromised peptide:protease (trypsin) binding (≥10 kcal/mol). The relative distance between scissile peptide carbonyl catalytic triad (H57, D102, S195) was found be significantly altered D-peptide:protease complex (inactive conformation) active L-peptide:protease complex. Thus, poor D-peptides protease, resulting inactive formation, explained experimentally observed proteolytic stability. This mechanistic insight might extended stability general stimulate rational design protease-resistant AMPs.

Language: Английский

Citations

5
Design of D-Amino Acids SARS-CoV-2 Main Protease Inhibitors Using the Cationic Peptide from Rattlesnake Venom as a Scaffold DOI Creative Commons
Raphael J. Eberle, Ian Gering, Markus Tusche

et al.

Pharmaceuticals, Journal Year: 2022, Volume and Issue: 15(5), P. 540 - 540

Published: April 27, 2022

The C30 endopeptidase (3C-like protease; 3CLpro) is essential for the life cycle of SARS-CoV-2 (severe acute respiratory syndrome-coronavirus-2) since it plays a pivotal role in viral replication and transcription and, hence, promising drug target. Molecules isolated from animals, insects, plants, or microorganisms can serve as scaffold design novel biopharmaceutical products. Crotamine, small cationic peptide venom rattlesnake Crotalus durissus terrificus, has been focus many studies exhibits activities such analgesic, vitro antibacterial, hemolytic activities. crotamine derivative L-peptides (L-CDP) that inhibit 3CL protease low µM range were examined they are susceptible to proteolytic degradation; we explored utility their D-enantiomers form. Comparative uptake inhibition analysis showed D-CDP prototype D-peptide-based drug. We also found D-peptides impair vivo, probably targeting 3CLpro.

Language: Английский

Citations

14
Rational Discovery of Antiviral Whey Protein-Derived Small Peptides Targeting the SARS-CoV-2 Main Protease DOI Creative Commons
Nicola Gambacorta, Leonardo Caputo, Laura Quintieri

et al.

Biomedicines, Journal Year: 2022, Volume and Issue: 10(5), P. 1067 - 1067

Published: May 4, 2022

In the present work, and for first time, three whey protein-derived peptides (IAEK, IPAVF, MHI), endowed with ACE inhibitory activity, were examined their antiviral activity against SARS-CoV-2 3C-like protease (3CLpro) Human Rhinovirus 3C (3Cpro) by employing molecular docking. Computational studies showed reliable binding poses within 3CLpro investigated small peptides, considering docking scores as well free energy values. Validation in vitro experiments confirmed these results. particular, IPAVF exhibited highest returning an IC50 equal to 1.21 μM; it was followed IAEK, which registered of 154.40 μM, whereas MHI less active 2700.62 μM. On other hand, none assayed 3Cpro. Based on results, herein presented are introduced promising molecules be exploited development "target-specific antiviral" agents SARS-CoV-2.

Language: Английский

Citations

13
Effective Inhibition of Thyroid Antigen Presentation Using Retro-Inverso Peptides in Experimental Autoimmune Thyroiditis: A Pathway Toward Immune Therapies of Thyroid Autoimmunity DOI

Cheuk Wun Li,

Roman Osman,

Francesca Menconi

et al.

Thyroid, Journal Year: 2023, Volume and Issue: 33(4), P. 492 - 500

Published: Feb. 10, 2023

Background: Autoimmune thyroid diseases (AITD) represent the most common autoimmune diseases. However, current therapies focus on relieving symptoms instead of curing AITD, and new to reverse attack are needed. HLA-DRβ1-Arg74 is key HLA class II allele that triggers AITD by presenting pathogenic thyroglobulin (Tg) peptides activate self-reactive T cells. We hypothesized blocking presentation Tg cells within peptide binding cleft could response in AITD. Methods: The approach we used block design retro-inverso D-amino acid (RID) have high affinity pocket. Results: By using computational approaches molecular dynamics simulations, designed two RID peptides, RT-15 VT-15, blocked recombinant molecule, as well cell activation vitro. Furthermore, VT-15 vivo humanized NOD-DR3 mice induced with experimental thyroiditis. Conclusions: In summary, discovered their These findings set stage for a personalized medicine therapeutic patients who carry DRβ1-Arg74 allele. This antigen-specific strategy can potentially be extended other

Language: Английский

Citations

5
Highly efficient discovery of the covalent M pro inhibitors from crude Pu-erh tea by integrating biochemical and chemoproteomic approaches DOI Creative Commons
Guanghao Zhu, Yani Zhang, Shenglan Qi

et al.

Deleted Journal, Journal Year: 2024, Volume and Issue: unknown

Published: June 1, 2024

The main proteases (Mpros) are hydrolases playing essential roles in the replication of β-coronaviruses including SARS-CoV-2. Herein, a highly efficient strategy was developed for discovering Mpro inactivators from crude plant extract integrating target-based biochemical assay and chemoproteomic approaches. Firstly, Pu-erh tea found to potently suppress SARS-CoV-2 time-dependent manner. Next, global chemical analysis coupling with peptide-modification profiling were used identify cysteine-modified constituents tea. results suggested that seven could modify Mpro, which turned out epigallocatechin, gallocatechin gallic acid most efficacious inactivators. Further investigations demonstrated epigallocatechin inactivate via blocking formation homodimers. Collectively, this work proposed novel practical discovery inhibitors extracts, while three have emerged as robust

Language: Английский

Citations

0
Discovery of all-D-peptide inhibitors of SARS CoV 2 3C-like protease DOI Creative Commons
Raphael J. Eberle, Marc Sevenich, Ian Gering

et al.

Published: June 14, 2022

During the replication process of SARS-CoV-2 main protease virus (3-chymotrypsin-like (3CLpro)) plays a pivotal role and is essential for life cycle pathogen. Numerous studies have been conducted so far, which confirmed 3CLpro as an attractive drug target to combat COVID-19. We describe novel efficient next generation sequencing (NGS) supported phage display selection strategy identification set targeting peptide ligands that inhibit 3CL protease, in competitive or non-competetive mode, low µM range. From most L-peptides obtained from display, we designed all-D-peptides based on retro-inverso (ri) principle. They had IC50 values also range, combination even sub-micromolar The inhibition modes these D-ri peptides were same their respective L-peptide versions. Our results demonstrate interact with high-affinity thus reinforcing potential therapeutic agents. here described address limitations associated current inhibitors are promising lead compounds. Further optimization regarding pharmacokinetic properties will allow development more potent D-peptides be used prevention treatment

Language: Английский

Citations

1