Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 20 de 42
Filter
1.
Int J Mol Sci ; 24(10)2023 May 15.
Article in English | MEDLINE | ID: covidwho-20233610

ABSTRACT

Though the bulk of the COVID-19 pandemic is behind, the search for effective and safe anti-SARS-CoV-2 drugs continues to be relevant. A highly pursued approach for antiviral drug development involves targeting the viral spike (S) protein of SARS-CoV-2 to prevent its attachment to the cellular receptor ACE2. Here, we exploited the core structure of polymyxin B, a naturally occurring antibiotic, to design and synthesize unprecedented peptidomimetics (PMs), intended to target contemporarily two defined, non-overlapping regions of the S receptor-binding domain (RBD). Monomers 1, 2, and 8, and heterodimers 7 and 10 bound to the S-RBD with micromolar affinity in cell-free surface plasmon resonance assays (KD ranging from 2.31 µM to 2.78 µM for dimers and 8.56 µM to 10.12 µM for monomers). Although the PMs were not able to fully protect cell cultures from infection with authentic live SARS-CoV-2, dimer 10 exerted a minimal but detectable inhibition of SARS-CoV-2 entry in U87.ACE2+ and A549.ACE2.TMPRSS2+ cells. These results validated a previous modeling study and provided the first proof-of-feasibility of using medium-sized heterodimeric PMs for targeting the S-RBD. Thus, heterodimers 7 and 10 may serve as a lead for the development of optimized compounds, which are structurally related to polymyxin, with improved S-RBD affinity and anti-SARS-CoV-2 potential.


Subject(s)
COVID-19 , Peptidomimetics , Humans , SARS-CoV-2 , Peptidomimetics/pharmacology , Binding Sites , Angiotensin-Converting Enzyme 2/chemistry , Polymyxins , Pandemics , Protein Binding
2.
Int J Mol Sci ; 24(10)2023 May 11.
Article in English | MEDLINE | ID: covidwho-20244460

ABSTRACT

The papain-like protease (PLpro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) plays a critical role in the proteolytic processing of viral polyproteins and the dysregulation of the host immune response, providing a promising therapeutic target. Here, we report the structure-guide design of novel peptidomimetic inhibitors covalently targeting SARS-CoV-2 PLpro. The resulting inhibitors demonstrate submicromolar potency in the enzymatic assay (IC50 = 0.23 µM) and significant inhibition of SARS-CoV-2 PLpro in the HEK293T cells using a cell-based protease assay (EC50 = 3.61 µM). Moreover, an X-ray crystal structure of SARS-CoV-2 PLpro in complex with compound 2 confirms the covalent binding of the inhibitor to the catalytic residue cysteine 111 (C111) and emphasizes the importance of interactions with tyrosine 268 (Y268). Together, our findings reveal a new scaffold of SARS-CoV-2 PLpro inhibitors and provide an attractive starting point for further optimization.


Subject(s)
COVID-19 , Peptidomimetics , Humans , Peptidomimetics/pharmacology , HEK293 Cells , SARS-CoV-2 , Peptide Hydrolases , Protease Inhibitors/pharmacology , Antiviral Agents/pharmacology , Antiviral Agents/chemistry
3.
Eur J Med Chem ; 257: 115512, 2023 Sep 05.
Article in English | MEDLINE | ID: covidwho-2327200

ABSTRACT

A series of peptidomimetic compounds containing benzothiazolyl ketone and [2.2.1] azabicyclic ring was designed, synthesized and evaluated in the hope of obtaining potent oral 3CLpro inhibitors with improved pharmacokinetic properties. Among the target compounds, 11b had the best enzymatic potency (IC50 = 0.110 µM) and 11e had the best microsomal stability (t1/2 > 120 min) and good enzyme activity (IC50 = 0.868 µM). Therefore, compounds 11b and 11e were chosen for further evaluation of pharmacokinetics in ICR mice. The results exhibited that the AUC(0-t) of 11e was 5143 h*ng/mL following single-dose oral administration of 20 mg/kg, and the F was 67.98%. Further structural modification was made to obtain compounds 11g-11j based on 11e. Among them, 11j exhibited the best enzyme inhibition activity against SARS-CoV-2 3CLpro (IC50 = 1.646 µM), the AUC(0-t) was 32473 h*ng/mL (20 mg/kg, po), and the F was 48.1%. In addition, 11j displayed significant anti-SARS-CoV-2 activity (EC50 = 0.18 µM) and low cytotoxicity (CC50 > 50 µM) in Vero E6 cells. All of the above results suggested that compound 11j was a promising lead compound in the development of oral 3CLpro inhibitors and deserved further research.


Subject(s)
COVID-19 , Peptidomimetics , Animals , Mice , Peptidomimetics/pharmacology , Peptidomimetics/chemistry , SARS-CoV-2 , Protease Inhibitors/chemistry , Ketones , Mice, Inbred ICR , Antiviral Agents/chemistry
4.
Bioorg Med Chem ; 87: 117316, 2023 05 03.
Article in English | MEDLINE | ID: covidwho-2320928

ABSTRACT

In this paper, a series of peptidomimetic SARS-CoV-2 3CL protease inhibitors with new P2 and P4 positions were synthesized and evaluated. Among these compounds, 1a and 2b exhibited obvious 3CLpro inhibitory activities with IC50 of 18.06 nM and 22.42 nM, respectively. 1a and 2b also showed excellent antiviral activities against SARS-CoV-2 in vitro with EC50 of 313.0 nM and 170.2 nM, respectively, the antiviral activities of 1a and 2b were 2- and 4-fold better than that of nirmatrelvir, respectively. In vitro studies revealed that these two compounds had no significant cytotoxicity. Further metabolic stability tests and pharmacokinetic studies showed that the metabolic stability of 1a and 2b in liver microsomes was significantly improved, and 2b had similar pharmacokinetic parameters to that of nirmatrelvir in mice.


Subject(s)
COVID-19 , Peptidomimetics , Animals , Mice , Protease Inhibitors/pharmacology , Peptidomimetics/pharmacology , SARS-CoV-2 , Nitriles , Antiviral Agents/pharmacology
5.
Eur J Med Chem ; 253: 115311, 2023 May 05.
Article in English | MEDLINE | ID: covidwho-2304178

ABSTRACT

Despite the approval of vaccines, monoclonal antibodies and restrictions during the pandemic, the demand for new efficacious and safe antivirals is compelling to boost the therapeutic arsenal against the COVID-19. The viral 3-chymotrypsin-like protease (3CLpro) is an essential enzyme for replication with high homology in the active site across CoVs and variants showing an almost unique specificity for Leu-Gln as P2-P1 residues, allowing the development of broad-spectrum inhibitors. The design, synthesis, biological activity, and cocrystal structural information of newly conceived peptidomimetic covalent reversible inhibitors are herein described. The inhibitors display an aldehyde warhead, a Gln mimetic at P1 and modified P2-P3 residues. Particularly, functionalized proline residues were inserted at P2 to stabilize the ß-turn like bioactive conformation, modulating the affinity. The most potent compounds displayed low/sub-nM potency against the 3CLpro of SARS-CoV-2 and MERS-CoV and inhibited viral replication of three human CoVs, i.e. SARS-CoV-2, MERS-CoV, and HCoV 229 in different cell lines. Particularly, derivative 12 exhibited nM-low µM antiviral activity depending on the virus, and the highest selectivity index. Some compounds were co-crystallized with SARS-CoV-2 3CLpro validating our design. Altogether, these results foster future work toward broad-spectrum 3CLpro inhibitors to challenge CoVs related pandemics.


Subject(s)
COVID-19 , Middle East Respiratory Syndrome Coronavirus , Peptidomimetics , Humans , SARS-CoV-2 , Protease Inhibitors/chemistry , Peptidomimetics/pharmacology , Peptidomimetics/chemistry , X-Rays , Peptide Hydrolases , Antiviral Agents/chemistry
6.
Molecules ; 28(6)2023 Mar 14.
Article in English | MEDLINE | ID: covidwho-2273373

ABSTRACT

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is responsible for COVID-19, which was declared a global pandemic in March 2020 by the World Health Organization (WHO). Since SARS-CoV-2 main protease plays an essential role in the virus's life cycle, the design of small drug molecules with lower molecular weight has been a promising development targeting its inhibition. Herein, we evaluated the novel peptidomimetic azatripeptide and azatetrapeptide nitriles against SARS-CoV-2 main protease. We employed molecular dynamics (MD) simulations to elucidate the selected compounds' binding free energy profiles against SARS-CoV-2 and further unveil the residues responsible for the drug-binding properties. Compound 8 exhibited the highest binding free energy of -49.37 ± 0.15 kcal/mol, followed by compound 7 (-39.83 ± 0.19 kcal/mol), while compound 17 showed the lowest binding free energy (-23.54 ± 0.19 kcal/mol). In addition, the absorption, distribution, metabolism, and excretion (ADME) assessment was performed and revealed that only compound 17 met the drug-likeness parameters and exhibited high pharmacokinetics to inhibit CYP1A2, CYP2C19, and CYP2C9 with better absorption potential and blood-brain barrier permeability (BBB) index. The additional intermolecular evaluations suggested compound 8 as a promising drug candidate for inhibiting SARS-CoV-2 Mpro. The substitution of isopropane in compound 7 with an aromatic benzene ring in compound 8 significantly enhanced the drug's ability to bind better at the active site of the SARS-CoV-2 Mpro.


Subject(s)
COVID-19 , Peptidomimetics , Humans , Peptidomimetics/pharmacology , SARS-CoV-2 , Molecular Dynamics Simulation , Esters/pharmacology , Molecular Docking Simulation , Protease Inhibitors
7.
J Pept Sci ; 29(5): e3467, 2023 May.
Article in English | MEDLINE | ID: covidwho-2248936

ABSTRACT

The COVID-19 pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is still affecting people worldwide. Despite the good degree of immunological protection achieved through vaccination, there are still severe cases that require effective antivirals. In this sense, two specific pharmaceutical preparations have been marketed already, the RdRp polymerase inhibitor molnupiravir and the main viral protease inhibitor nirmatrelvir (commercialized as Paxlovid, a combination with ritonavir). Nirmatrelvir is a peptidomimetic acting as orally available, covalent, and reversible inhibitor of SARS-CoV-2 main viral protease. The success of this compound has revitalized the search for new peptide and peptidomimetic protease inhibitors. This highlight collects some selected examples among those recently published in the field of SARS-CoV-2.


Subject(s)
COVID-19 , Peptidomimetics , Humans , Pandemics , Peptidomimetics/pharmacology , SARS-CoV-2 , Antiviral Agents/pharmacology , Peptides/pharmacology , Protease Inhibitors/pharmacology
8.
Indian J Pharmacol ; 55(1): 53-58, 2023.
Article in English | MEDLINE | ID: covidwho-2267521

ABSTRACT

Novel SARS-CoV-2 (COVID-19) is affecting worldwide as declared pandemic by the WHO. Various repositioning and novel therapeutic agents are being evaluated under different clinical setups; however, there is no promising therapeutic agent reported to date. Small molecules like peptides have their popularity as their specificity, delivery, and synthesizability as promising therapeutic agents. In this study, we have reviewed the published literature describing peptide designing, in silico binding mode, antiviral activity, preventive measures, and in vivo assessments. Here, we reported all the results which are promising against SARS-CoV-2 as therapeutic and preventive (vaccine candidates), and their status in the drug development process.


Subject(s)
COVID-19 , Peptidomimetics , Humans , SARS-CoV-2 , Peptidomimetics/pharmacology , Peptidomimetics/therapeutic use , Drug Repositioning , Antiviral Agents/therapeutic use , Antiviral Agents/chemistry , Peptides/therapeutic use
9.
Drug Discov Today ; 28(3): 103468, 2023 03.
Article in English | MEDLINE | ID: covidwho-2257250

ABSTRACT

The (re)emergence of multidrug-resistant viruses and the emergence of new viruses highlight the urgent and ongoing need for new antiviral agents. The use of peptidomimetics as therapeutic drugs has often been associated with advantages, such as enhanced binding affinity, improved metabolic stability, and good bioavailability profiles. The development of novel antivirals is currently driven by strategies of converting peptides into peptidomimetic derivatives. In this review, we outline different structural modification design strategies for developing novel peptidomimetics as antivirals, involving N- or C-cap terminal structure modifications, pseudopeptides, amino acid modifications, inverse-peptides, cyclization, and molecular hybridization. We also present successful recent examples of peptidomimetic designs.


Subject(s)
Peptidomimetics , Antiviral Agents , Chemistry, Pharmaceutical , Peptides/chemistry
10.
Viruses ; 14(9)2022 09 18.
Article in English | MEDLINE | ID: covidwho-2033152

ABSTRACT

The ongoing spread of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has caused hundreds of millions of cases and millions of victims worldwide with serious consequences to global health and economies. Although many vaccines protecting against SARS-CoV-2 are currently available, constantly emerging new variants necessitate the development of alternative strategies for prevention and treatment of COVID-19. Inhibitors that target the main protease (Mpro) of SARS-CoV-2, an essential enzyme that promotes viral maturation, represent a key class of antivirals. Here, we showed that a peptidomimetic compound with benzothiazolyl ketone as warhead, YH-53, is an effective inhibitor of SARS-CoV-2, SARS-CoV, and MERS-CoV Mpros. Crystal structures of Mpros from SARS-CoV-2, SARS-CoV, and MERS-CoV bound to the inhibitor YH-53 revealed a unique ligand-binding site, which provides new insights into the mechanism of inhibition of viral replication. A detailed analysis of these crystal structures defined the key molecular determinants required for inhibition and illustrate the binding mode of Mpros from other coronaviruses. In consideration of the important role of Mpro in developing antivirals against coronaviruses, insights derived from this study should add to the design of pan-coronaviral Mpro inhibitors that are safer and more effective.


Subject(s)
COVID-19 Drug Treatment , Middle East Respiratory Syndrome Coronavirus , Peptidomimetics , Antiviral Agents/chemistry , Benzothiazoles/pharmacology , Coronavirus 3C Proteases , Cysteine Endopeptidases/metabolism , Humans , Ketones , Ligands , Peptide Hydrolases , Protease Inhibitors/chemistry , SARS-CoV-2
11.
J Org Chem ; 87(18): 12041-12051, 2022 09 16.
Article in English | MEDLINE | ID: covidwho-2016521

ABSTRACT

The development of molecules able to target protein-protein interactions (PPIs) is of interest for the development of novel therapeutic agents. Since a high percentage of PPIs are mediated by α-helical structure at the interacting surface, peptidomimetics that reproduce the essential conformational components of helices are useful templates for the development of PPIs inhibitors. In this work, the synthesis of a constrained dipeptide isostere and insertion in the short peptide epitope EDLFYQ of the angiotensin-converting enzyme 2 (ACE2) α1 helix domain resulted in the identification of a molecule capable of inhibiting the SARS-CoV-2 ACE2/spike interaction in the micromolar range. Moreover, inhibition of SARS-CoV-2 3CLPro main protease activity was assessed as an additional inhibitory property of the synthesized peptidomimetics, taking advantage of the C-terminal Q amino acid present in both the ACE2 epitope and the Mpro recognizing motif (APSTVxLQ), thus paving the way to the development of multitarget therapeutics toward coronavirus infections.


Subject(s)
COVID-19 , Peptidomimetics , Amino Acids , Angiotensin-Converting Enzyme 2 , Dipeptides , Epitopes , Humans , Peptides/metabolism , Peptides/pharmacology , Peptidomimetics/pharmacology , Protein Binding , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/metabolism
12.
Eur J Med Chem ; 238: 114458, 2022 Aug 05.
Article in English | MEDLINE | ID: covidwho-1982956

ABSTRACT

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), as the pathogen of coronavirus disease 2019 (COVID-19), has infected millions of people and took hundreds of thousands of lives. Unfortunately, there is deficiency of effective medicines to prevent or treat COVID-19. 3C like protease (3CLPro) of SARS-CoV-2 is essential to the viral replication and transcription, and is an attractive target to develop anti-SARS-CoV-2 agents. Targeting on the 3CLPro, we screened our protease inhibitor library and obtained compound 10a as hit to weakly inhibit the SARS-CoV-2 3CLPro, and determined the co-crystal structure of 10a and the protease. Based on the deep understanding on the protein-ligand complexes between the hit and SARS-CoV-2 3CLPro, we designed a series of peptidomimetic inhibitors, with outstanding inhibitory activity against SARS-CoV-2 3CLPro and excellent anti-viral potency against SARS-CoV-2. The protein-ligand complexes of the other key inhibitors with SARS-CoV-2 3CLPro were explicitly described by the X-ray co-crystal study. All such results suggest these peptidomimetic inhibitors could be further applied as encouraging drug candidates.


Subject(s)
COVID-19 Drug Treatment , Peptidomimetics , Antiviral Agents/chemistry , Cysteine Endopeptidases/chemistry , Humans , Ligands , Peptide Hydrolases , Peptidomimetics/chemistry , Peptidomimetics/pharmacology , Protease Inhibitors/chemistry , SARS-CoV-2
13.
Commun Biol ; 5(1): 681, 2022 07 08.
Article in English | MEDLINE | ID: covidwho-1927105

ABSTRACT

The transmembrane serine protease 2 (TMPRSS2) primes the SARS-CoV-2 Spike (S) protein for host cell entry and represents a promising target for COVID-19 therapy. Here we describe the in silico development and in vitro characterization of peptidomimetic TMPRSS2 inhibitors. Molecular docking studies identified peptidomimetic binders of the TMPRSS2 catalytic site, which were synthesized and coupled to an electrophilic serine trap. The compounds inhibit TMPRSS2 while demonstrating good off-target selectivity against selected coagulation proteases. Lead candidates are stable in blood serum and plasma for at least ten days. Finally, we show that selected peptidomimetics inhibit SARS-CoV-2 Spike-driven pseudovirus entry and authentic SARS-CoV-2 infection with comparable efficacy as camostat mesylate. The peptidomimetic TMPRSS2 inhibitors also prevent entry of recent SARS-CoV-2 variants of concern Delta and Omicron BA.1. In sum, our study reports antivirally active and stable TMPRSS2 inhibitors with prospects for further preclinical and clinical development as antiviral agents against SARS-CoV-2 and other TMPRSS2-dependent viruses.


Subject(s)
COVID-19 Drug Treatment , Peptidomimetics , Cell Culture Techniques , Humans , Molecular Docking Simulation , Peptidomimetics/pharmacology , SARS-CoV-2 , Serine Endopeptidases/genetics
14.
PLoS One ; 17(6): e0269563, 2022.
Article in English | MEDLINE | ID: covidwho-1910663

ABSTRACT

SARS-CoV-2 causes the current global pandemic coronavirus disease 2019. Widely-available effective drugs could be a critical factor in halting the pandemic. The main protease (3CLpro) plays a vital role in viral replication; therefore, it is of great interest to find inhibitors for this enzyme. We applied the combination of virtual screening based on molecular docking derived from the crystal structure of the peptidomimetic inhibitors (N3, 13b, and 11a), and experimental verification revealed FDA-approved drugs that could inhibit the 3CLpro of SARS-CoV-2. Three drugs were selected using the binding energy criteria and subsequently performed the 3CLpro inhibition by enzyme-based assay. In addition, six common drugs were also chosen to study the 3CLpro inhibition. Among these compounds, lapatinib showed high efficiency of 3CLpro inhibition (IC50 value of 35 ± 1 µM and Ki of 23 ± 1 µM). The binding behavior of lapatinib against 3CLpro was elucidated by molecular dynamics simulations. This drug could well bind with 3CLpro residues in the five subsites S1', S1, S2, S3, and S4. Moreover, lapatinib's key chemical pharmacophore features toward SAR-CoV-2 3CLpro shared important HBD and HBA with potent peptidomimetic inhibitors. The rational design of lapatinib was subsequently carried out using the obtained results. Our discovery provides an effective repurposed drug and its newly designed analogs to inhibit SARS-CoV-2 3CLpro.


Subject(s)
COVID-19 Drug Treatment , Peptidomimetics , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Coronavirus 3C Proteases , Cysteine Endopeptidases/metabolism , Drug Repositioning , Humans , Lapatinib/pharmacology , Molecular Docking Simulation , Molecular Dynamics Simulation , Peptidomimetics/pharmacology , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , SARS-CoV-2
15.
Drug Des Devel Ther ; 16: 1067-1082, 2022.
Article in English | MEDLINE | ID: covidwho-1808738

ABSTRACT

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) currently poses a threat to human health. 3C-like proteinase (3CLpro) plays an important role in the viral life cycle. Hence, it is considered an attractive antiviral target protein. Whole-genome sequencing showed that the sequence homology between SARS-CoV-2 3CLpro and SARS-CoV 3CLpro is 96.08%, with high similarity in the substrate-binding region. Thus, assessing peptidomimetic inhibitors of SARS-CoV 3CLpro could accelerate the development of peptidomimetic inhibitors for SARS-CoV-2 3CLpro. Accordingly, we herein discuss progress on SARS-CoV-2 3CLpro peptidomimetic inhibitors. Inflammation plays a major role in the pathophysiological process of COVID-19. Small-molecule compounds targeting 3CLpro with both antiviral and anti-inflammatory effects are also briefly discussed in this paper.


Subject(s)
Antiviral Agents , COVID-19 Drug Treatment , Coronavirus 3C Proteases , Peptidomimetics , Protease Inhibitors , Anti-Inflammatory Agents/pharmacology , Antiviral Agents/pharmacology , Coronavirus 3C Proteases/antagonists & inhibitors , Humans , Peptidomimetics/pharmacology , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , SARS-CoV-2
16.
Expert Opin Drug Discov ; 17(6): 547-557, 2022 06.
Article in English | MEDLINE | ID: covidwho-1740670

ABSTRACT

INTRODUCTION: The main cysteine protease from SARS-CoV-2 (Mpro), conserved among many pathogenic coronaviruses, represents a recently validated antiviral drug target, with at least one inhibitor recently approved for clinical use as an antiviral drug, nirmatrelvir (paxlovidTM). AREAS COVERED: The authors review the scientific literature on the drug design landscape of α-ketoamide SARS-CoV-2 Mpro inhibitors. The X-ray/neutron crystal structure of three such compounds is available, which has allowed for drug design rationalization. The α-ketoamide functionality of the inhibitors reacts with the catalytic dyad cysteine residue to form a hemithioketal. The S3, S2, and S1' subsites of the protease are filled with various aromatic or aliphatic (cyclic/acyclic) moieties of the peptidomimetic, whereas in S1, the preferred moiety was a rigid 2-pyrrolidone or norvaline side chain (as in telaprevir). EXPERT OPINION: Crystallography, previous drug design efforts, and many computational studies have allowed for a deeper understanding of the structural requirements needed for designing effective SARS-CoV-2 Mpro α-ketoamide inhibitors. However, all the reported derivatives are peptidomimetics with a rather high molecular weight. It is expected that effective compounds with lower molecular weights and a lesser peptidomimetic profile will be the target for future drug development.


Subject(s)
COVID-19 Drug Treatment , Peptidomimetics , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Coronavirus 3C Proteases , Cysteine Endopeptidases/chemistry , Humans , Peptidomimetics/pharmacology , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , SARS-CoV-2
17.
J Med Chem ; 65(4): 2880-2904, 2022 02 24.
Article in English | MEDLINE | ID: covidwho-1705973

ABSTRACT

Starting from the MLPCN probe compound ML300, a structure-based optimization campaign was initiated against the recent severe acute respiratory syndrome coronavirus (SARS-CoV-2) main protease (3CLpro). X-ray structures of SARS-CoV-1 and SARS-CoV-2 3CLpro enzymes in complex with multiple ML300-based inhibitors, including the original probe ML300, were obtained and proved instrumental in guiding chemistry toward probe compound 41 (CCF0058981). The disclosed inhibitors utilize a noncovalent mode of action and complex in a noncanonical binding mode not observed by peptidic 3CLpro inhibitors. In vitro DMPK profiling highlights key areas where further optimization in the series is required to obtain useful in vivo probes. Antiviral activity was established using a SARS-CoV-2-infected Vero E6 cell viability assay and a plaque formation assay. Compound 41 demonstrates nanomolar activity in these respective assays, comparable in potency to remdesivir. These findings have implications for antiviral development to combat current and future SARS-like zoonotic coronavirus outbreaks.


Subject(s)
Antiviral Agents/pharmacology , Coronavirus 3C Proteases/antagonists & inhibitors , Cysteine Proteinase Inhibitors/pharmacology , Peptidomimetics/pharmacology , SARS-CoV-2/drug effects , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , COVID-19/metabolism , Chlorocebus aethiops , Coronavirus 3C Proteases/isolation & purification , Coronavirus 3C Proteases/metabolism , Crystallography, X-Ray , Cysteine Proteinase Inhibitors/chemical synthesis , Cysteine Proteinase Inhibitors/chemistry , Dose-Response Relationship, Drug , Glutamine/chemistry , Glutamine/pharmacology , Humans , Ketones/chemistry , Ketones/pharmacology , Microbial Sensitivity Tests , Models, Molecular , Molecular Structure , Peptidomimetics/chemistry , SARS-CoV-2/enzymology , Vero Cells , Virus Replication/drug effects , COVID-19 Drug Treatment
18.
Mol Inform ; 41(7): e2100231, 2022 07.
Article in English | MEDLINE | ID: covidwho-1648973

ABSTRACT

BACKGROUND: Coronavirus disease 2019 (COVID-19) as global pandemic disease has been adversely affecting public health and social life with considerable loss of human life worldwide. Therefore, there is an urgent need for developing novel therapeutics to combat COVID-19. The causative agent of COVID-19 is SARS-CoV-2 which targets human angiotensin converting enzyme 2 (ACE2) as cellular receptor via its spike (S) protein. In this context, interfering with the binding of SARS-CoV-2 S protein to target molecules could provide a promising strategy to find novel therapeutic agents against SARS-CoV-2. The purpose of the current study was to identify potential peptidomimetics against S protein with a combination of structure-based virtual screening methods and in vitro assays. METHODS: The candidates were inspected in terms of ADME properties, drug-likeness, as well as toxicity profiles. Additionally, molecular docking and dynamics simulations were performed to predict binding of the studied ligands to spike protein. RESULTS: Biological evaluation of the compounds revealed that PM2 molecule exhibits some antiviral activity. CONCLUSION: In summary, this study highlights the importance of combining in silico and in vitro techniques in order to identify antiviral compound to tackle COVID-19 and presents a new scaffold that may be structurally optimized for improved antiviral activity.


Subject(s)
Antiviral Agents , Peptidomimetics , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Antiviral Agents/chemistry , Molecular Docking Simulation , Peptidomimetics/pharmacology , SARS-CoV-2/drug effects , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Spike Glycoprotein, Coronavirus/chemistry
19.
Chem Commun (Camb) ; 58(11): 1804-1807, 2022 Feb 03.
Article in English | MEDLINE | ID: covidwho-1639537

ABSTRACT

We present the finding of a dimeric ACE2 peptide mimetic designed through side chain cross-linking and covalent dimerization. It has a binding affinity of 16 nM for the SARS-CoV-2 spike RBD, and effectively inhibits the SARS-CoV-2 pseudovirus in Huh7-hACE2 cells with an IC50 of 190 nM and neutralizes the authentic SARS-CoV-2 in Caco2 cells with an IC50 of 2.4 µM. Our study should provide a new insight for the optimization of peptide-based anti-SARS-CoV-2 inhibitors.


Subject(s)
Antiviral Agents/pharmacology , Peptide Fragments/pharmacology , Peptidomimetics/pharmacology , SARS-CoV-2/drug effects , Amino Acid Sequence , Angiotensin-Converting Enzyme 2/chemistry , Antiviral Agents/chemical synthesis , Antiviral Agents/metabolism , Cell Line, Tumor , Humans , Microbial Sensitivity Tests , Peptide Fragments/chemical synthesis , Peptide Fragments/metabolism , Peptidomimetics/chemical synthesis , Peptidomimetics/metabolism , Protein Binding , Protein Domains , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/metabolism
20.
Int J Mol Sci ; 22(21)2021 Oct 29.
Article in English | MEDLINE | ID: covidwho-1488616

ABSTRACT

After almost two years from its first evidence, the COVID-19 pandemic continues to afflict people worldwide, highlighting the need for multiple antiviral strategies. SARS-CoV-2 main protease (Mpro/3CLpro) is a recognized promising target for the development of effective drugs. Because single target inhibition might not be sufficient to block SARS-CoV-2 infection and replication, multi enzymatic-based therapies may provide a better strategy. Here we present a structural and biochemical characterization of the binding mode of MG-132 to both the main protease of SARS-CoV-2, and to the human Cathepsin-L, suggesting thus an interesting scaffold for the development of double-inhibitors. X-ray diffraction data show that MG-132 well fits into the Mpro active site, forming a covalent bond with Cys145 independently from reducing agents and crystallization conditions. Docking of MG-132 into Cathepsin-L well-matches with a covalent binding to the catalytic cysteine. Accordingly, MG-132 inhibits Cathepsin-L with nanomolar potency and reversibly inhibits Mpro with micromolar potency, but with a prolonged residency time. We compared the apo and MG-132-inhibited structures of Mpro solved in different space groups and we identified a new apo structure that features several similarities with the inhibited ones, offering interesting perspectives for future drug design and in silico efforts.


Subject(s)
COVID-19 Drug Treatment , Cathepsin L/drug effects , Coronavirus 3C Proteases/drug effects , Leupeptins/chemistry , Leupeptins/pharmacology , SARS-CoV-2/chemistry , SARS-CoV-2/drug effects , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Catalytic Domain/drug effects , Cathepsin L/chemistry , Coronavirus 3C Proteases/chemistry , Drug Design , Drug Discovery , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , Peptidomimetics , Protein Binding , Protein Conformation , Protein Interaction Domains and Motifs , Virus Replication/drug effects , X-Ray Diffraction
SELECTION OF CITATIONS
SEARCH DETAIL