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Journal of Global Antimicrobial... Jun 2022In low-middle-income countries, increasing levels of HIV drug resistance (HIVDR) on second-line protease inhibitor (PI)-based regimens are a cause for concern given the...
OBJECTIVES
In low-middle-income countries, increasing levels of HIV drug resistance (HIVDR) on second-line protease inhibitor (PI)-based regimens are a cause for concern given the limited drug options for third-line antiretroviral therapy (ART). We conducted a retrospective analysis of routine HIV-1 genotyping laboratory data from KwaZulu-Natal, South Africa, to describe the frequency and patterns of HIVDR mutations and their consequent impact on standardised third-line regimens.
METHODS
This was a cross-sectional analysis of all HIV-1 genotypic resistance tests conducted by the National Health Laboratory Service in KwaZulu-Natal (January 2015 to December 2016) for adults and adolescents (age ≥10 years) on second-line PI-based ART with virological failure. We assigned a third-line regimen to each record based on a national treatment algorithm and calculated the genotypic susceptibility score (GSS) for that regimen.
RESULTS
Of 348 samples analysed, 287 (82.5%) had at least one drug resistance mutation (DRM) and 114 (32.8%) had at least one major PI DRM. Major PI resistance was associated with longer duration on second-line ART (aOR per 6-months = 1.11, 95% CI 1.04-1.19) and older age (aOR = 1.03, 95% CI 1.01-1.05). Of 112 patients requiring third-line ART, 12 (10.7%) had a GSS of <2 for the algorithm-assigned third-line regimen.
CONCLUSION
One-third of people failing second-line ART had significant PI DRMs. A subgroup of these individuals had extensive HIVDR, where the predicted activity of third-line ART was suboptimal, highlighting the need for continuous evaluation of outcomes on third-line regimens and close monitoring for emergent HIV-1 integrase inhibitor resistance.
Topics: Adolescent; Adult; Anti-HIV Agents; Child; Cross-Sectional Studies; Drug Resistance, Viral; HIV Infections; HIV-1; Humans; Protease Inhibitors; Retrospective Studies; South Africa
PubMed: 34785393
DOI: 10.1016/j.jgar.2021.10.023 -
Science Translational Medicine Mar 2024Inhibitors of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (M) such as nirmatrelvir (NTV) and ensitrelvir (ETV) have proven effective...
Inhibitors of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (M) such as nirmatrelvir (NTV) and ensitrelvir (ETV) have proven effective in reducing the severity of COVID-19, but the presence of resistance-conferring mutations in sequenced viral genomes raises concerns about future drug resistance. Second-generation oral drugs that retain function against these mutants are thus urgently needed. We hypothesized that the covalent hepatitis C virus protease inhibitor boceprevir (BPV) could serve as the basis for orally bioavailable drugs that inhibit SARS-CoV-2 M more efficiently than existing drugs. Performing structure-guided modifications of BPV, we developed a picomolar-affinity inhibitor, ML2006a4, with antiviral activity, oral pharmacokinetics, and therapeutic efficacy similar or superior to those of NTV. A crucial feature of ML2006a4 is a derivatization of the ketoamide reactive group that improves cell permeability and oral bioavailability. Last, ML2006a4 was found to be less sensitive to several mutations that cause resistance to NTV or ETV and occur in the natural SARS-CoV-2 population. Thus, anticipatory design can preemptively address potential resistance mechanisms to expand future treatment options against coronavirus variants.
Topics: Humans; COVID-19; SARS-CoV-2; Mutation; Antiviral Agents; Protease Inhibitors; Coronavirus 3C Proteases
PubMed: 38478629
DOI: 10.1126/scitranslmed.adi0979 -
Molecular Factors and Pathways of Hepatotoxicity Associated with HIV/SARS-CoV-2 Protease Inhibitors.International Journal of Molecular... Apr 2023Antiviral protease inhibitors are peptidomimetic molecules that block the active catalytic center of viral proteases and, thereby, prevent the cleavage of viral... (Review)
Review
Antiviral protease inhibitors are peptidomimetic molecules that block the active catalytic center of viral proteases and, thereby, prevent the cleavage of viral polyprotein precursors into maturation. They continue to be a key class of antiviral drugs that can be used either as boosters for other classes of antivirals or as major components of current regimens in therapies for the treatment of infections with human immunodeficiency virus (HIV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, sustained/lifelong treatment with the drugs or drugs combined with other substance(s) often leads to severe hepatic side effects such as lipid abnormalities, insulin resistance, and hepatotoxicity. The underlying pathogenic mechanisms are not fully known and are under continuous investigation. This review focuses on the general as well as specific molecular mechanisms of the protease inhibitor-induced hepatotoxicity involving transporter proteins, apolipoprotein B, cytochrome P450 isozymes, insulin-receptor substrate 1, Akt/PKB signaling, lipogenic factors, UDP-glucuronosyltransferase, pregnane X receptor, hepatocyte nuclear factor 4α, reactive oxygen species, inflammatory cytokines, off-target proteases, and small GTPase Rab proteins related to ER-Golgi trafficking, organelle stress, and liver injury. Potential pharmaceutical/therapeutic solutions to antiviral drug-induced hepatic side effects are also discussed.
Topics: Humans; SARS-CoV-2; COVID-19; HIV Protease Inhibitors; Protease Inhibitors; Antiviral Agents; HIV Infections; Chemical and Drug Induced Liver Injury
PubMed: 37175645
DOI: 10.3390/ijms24097938 -
International Journal of Molecular... Feb 2024Predicting the potency of inhibitors is key to in silico screening of promising synthetic or natural compounds. Here we describe a predictive workflow that provides...
Predicting the potency of inhibitors is key to in silico screening of promising synthetic or natural compounds. Here we describe a predictive workflow that provides calculated inhibitory values, which concord well with empirical data. Calculations of the free interaction energy ΔG with the YASARA plugin FoldX were used to derive inhibition constants K from PDB coordinates of protease-inhibitor complexes. At the same time, corresponding K values were obtained from the PRODIGY server. These results correlated well with the experimental values, particularly for serine proteases. In addition, analyses were performed for inhibitory complexes of cysteine and aspartic proteases, as well as of metalloproteases, whereby the PRODIGY data appeared to be more consistent. Based on our analyses, we calculated theoretical K values for trypsin with sunflower trypsin inhibitor (SFTI-1) variants, which yielded the more rigid Pro14 variant, with probably higher potency than the wild-type inhibitor. Moreover, a hirudin variant with an Arg1 and Trp3 is a promising basis for novel thrombin inhibitors with high potency. Further examples from antibody interaction and a cancer-related effector-receptor system demonstrate that our approach is applicable to protein interaction studies beyond the protease field.
Topics: Serine Endopeptidases; Trypsin Inhibitors; Trypsin; Helianthus; Peptide Hydrolases; Protease Inhibitors
PubMed: 38397107
DOI: 10.3390/ijms25042429 -
Journal of Medicinal Chemistry Dec 2023The ongoing transmission of SARS-CoV-2 necessitates the development of additional potent antiviral agents capable of combating the current highly infectious variants and...
Design, Synthesis, and Biological Evaluation of Trisubstituted Piperazine Derivatives as Noncovalent Severe Acute Respiratory Syndrome Coronavirus 2 Main Protease Inhibitors with Improved Antiviral Activity and Favorable Druggability.
The ongoing transmission of SARS-CoV-2 necessitates the development of additional potent antiviral agents capable of combating the current highly infectious variants and future coronaviruses. Here, we present the discovery of potent nonpeptide main protease (M) inhibitors with prominent antiviral activity and improved pharmacokinetic properties. Three series of 1,2,4-trisubstituted piperazine derivatives were designed and synthesized, and the optimal demonstrated high enzyme-inhibitory potency (IC = 0.19 μM) and exhibited excellent antiviral activity (EC = 0.40 μM), reaching the same level as Nirmatrelvir (EC = 0.38 μM). Additionally, displayed potent antiviral activities against various SARS-CoV-2 variants as well as HCoV-OC43 and HCoV-229E, indicating its potential broad-spectrum anticoronaviral activity. Notably, the pharmacokinetic properties of were somewhat enhanced compared to those of the lead compound. Furthermore, the cocrystal and molecular docking elucidated the mechanism of action. In conclusion, we discovered a novel nonpeptidic M inhibitor with promising antiviral activity and a favorable pharmacokinetic profile.
Topics: Humans; SARS-CoV-2; COVID-19; Molecular Docking Simulation; Protease Inhibitors; Antiviral Agents; Piperazines
PubMed: 37992202
DOI: 10.1021/acs.jmedchem.3c01876 -
Drug Discovery Today Jun 2023The severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) is the causative factor behind the 2019 global coronavirus pandemic (COVID-19). The main protease, known... (Review)
Review
The severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) is the causative factor behind the 2019 global coronavirus pandemic (COVID-19). The main protease, known as M, is encoded by the viral genome and is essential for viral replication. It has also been an effective target for drug development. In this review, we discuss the rationale for inhibitors that specifically target SARS-CoV-2 M. Small molecules and peptidomimetic inhibitors are two types of inhibitor with various modes of action and we focus here on novel inhibitors that were only discovered during the COVID-19 pandemic highlighting their binding modes and structures.
Topics: Humans; COVID-19; SARS-CoV-2; Pandemics; Antiviral Agents; Drug Development; Protease Inhibitors; Molecular Docking Simulation
PubMed: 37028502
DOI: 10.1016/j.drudis.2023.103579 -
International Journal of Molecular... May 2020In the past 17 years, three novel coronaviruses have caused severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and the coronavirus... (Review)
Review
In the past 17 years, three novel coronaviruses have caused severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and the coronavirus disease 2019 (COVID-19). As emerging infectious diseases, they were characterized by their novel pathogens and transmissibility without available clinical drugs or vaccines. This is especially true for the newly identified COVID-19 caused by SARS coronavirus 2 (SARS-CoV-2) for which, to date, no specific antiviral drugs or vaccines have been approved. Similar to SARS and MERS, the lag time in the development of therapeutics is likely to take months to years. These facts call for the development of broad-spectrum anti-coronavirus drugs targeting a conserved target site. This review will systematically describe potential broad-spectrum coronavirus fusion inhibitors, including antibodies, protease inhibitors, and peptide fusion inhibitors, along with a discussion of their advantages and disadvantages.
Topics: Animals; Betacoronavirus; Coronavirus Infections; Humans; Protease Inhibitors; SARS-CoV-2; Viral Fusion Protein Inhibitors; Virus Internalization
PubMed: 32481690
DOI: 10.3390/ijms21113843 -
FEBS Letters Dec 2021Interleukin-6 (IL-6) and interleukin-11 (IL-11) are two important pleiotropic cytokines, both of which signal through a homodimer of the β-receptor gp130. Specificity...
Interleukin-6 (IL-6) and interleukin-11 (IL-11) are two important pleiotropic cytokines, both of which signal through a homodimer of the β-receptor gp130. Specificity is gained through the unique, nonsignaling α-receptors IL-6R and IL-11R. Soluble variants of IL-6R and IL-11R also exist. Both membrane-bound receptors can be cleaved by the metalloprotease ADAM10. Here, we use ten different chimeric receptors consisting of different parts of IL-6R and IL-11R and analyze their susceptibility toward cleavage by ADAM10. As expected, all chimeras are substrates of ADAM10. However, we observed that cleavage of chimeric receptors containing the stalk region of the IL-11R could be blocked by the protease inhibitor GI (selective for ADAM10), but not by the protease inhibitor GW (selective for both ADAM10 and ADAM17), suggesting that another protease besides ADAM10 is involved in cleavage of these chimeras.
Topics: ADAM10 Protein; HEK293 Cells; Humans; Interleukin-6; Ionomycin; Protease Inhibitors; Proteolysis; Receptors, Interleukin-11; Recombinant Fusion Proteins
PubMed: 34778975
DOI: 10.1002/1873-3468.14230 -
Journal of Virology Apr 2022The high mutation rate of COVID-19 and the prevalence of multiple variants strongly support the need for pharmacological options to complement vaccine strategies. One...
The high mutation rate of COVID-19 and the prevalence of multiple variants strongly support the need for pharmacological options to complement vaccine strategies. One region that appears highly conserved among different genera of coronaviruses is the substrate-binding site of the main protease (M or 3CL), making it an attractive target for the development of broad-spectrum drugs for multiple coronaviruses. PF-07321332, developed by Pfizer, is the first orally administered inhibitor targeting the main protease of SARS-CoV-2, which also has shown potency against other coronaviruses. Here, we report three crystal structures of the main protease of SARS-CoV-2, SARS-CoV, and Middle East respiratory syndrome (MERS)-CoV bound to the inhibitor PF-07321332. The structures reveal a ligand-binding site that is conserved among SARS-CoV-2, SARS-CoV, and MERS-CoV, providing insights into the mechanism of inhibition of viral replication. The long and narrow cavity in the cleft between domains I and II of the main protease harbors multiple inhibitor-binding sites, where PF-07321332 occupies subsites S1, S2, and S4 and appears more restricted than other inhibitors. A detailed analysis of these structures illuminated key structural determinants essential for inhibition and elucidated the binding mode of action of the main proteases from different coronaviruses. Given the importance of the main protease for the treatment of SARS-CoV-2 infection, insights derived from this study should accelerate the design of safer and more effective antivirals. The current pandemic of multiple variants has created an urgent need for effective inhibitors of SARS-CoV-2 to complement vaccine strategies. PF-07321332, developed by Pfizer, is the first orally administered coronavirus-specific main protease inhibitor approved by the FDA. We solved the crystal structures of the main protease of SARS-CoV-2, SARS-CoV, and MERS-CoV that bound to the PF-07321332, suggesting PF-07321332 is a broad-spectrum inhibitor for coronaviruses. Structures of the main protease inhibitor complexes present an opportunity to discover safer and more effective inhibitors for COVID-19.
Topics: Antiviral Agents; Humans; Lactams; Leucine; Middle East Respiratory Syndrome Coronavirus; Nitriles; Peptide Hydrolases; Proline; Protease Inhibitors; Severe acute respiratory syndrome-related coronavirus; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 35389231
DOI: 10.1128/jvi.02013-21 -
International Journal of Molecular... Apr 2023The latest monkeypox virus outbreak in 2022 showcased the potential threat of this viral zoonosis to public health. The lack of specific treatments against this...
The latest monkeypox virus outbreak in 2022 showcased the potential threat of this viral zoonosis to public health. The lack of specific treatments against this infection and the success of viral protease inhibitors-based treatments against HIV, Hepatitis C, and SARS-CoV-2, brought the monkeypox virus I7L protease under the spotlight as a potential target for the development of specific and compelling drugs against this emerging disease. In the present work, the structure of the monkeypox virus I7L protease was modeled and thoroughly characterized through a dedicated computational study. Furthermore, structural information gathered in the first part of the study was exploited to virtually screen the DrugBank database, consisting of drugs approved by the Food and Drug Administration (FDA) and clinical-stage drug candidates, in search for readily repurposable compounds with similar binding features as TTP-6171, the only non-covalent I7L protease inhibitor reported in the literature. The virtual screening resulted in the identification of 14 potential inhibitors of the monkeypox I7L protease. Finally, based on data collected within the present work, some considerations on developing allosteric modulators of the I7L protease are reported.
Topics: Humans; SARS-CoV-2; COVID-19; Pharmaceutical Preparations; Peptide Hydrolases; Molecular Docking Simulation; Viral Nonstructural Proteins; Cysteine Endopeptidases; Antiviral Agents; Protease Inhibitors; Molecular Dynamics Simulation; Drug Repositioning
PubMed: 37108279
DOI: 10.3390/ijms24087119