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1.
Nature ; 605(7908): 146-151, 2022 05.
Article in English | MEDLINE | ID: covidwho-1815561

ABSTRACT

Coronavirus disease 2019 (COVID-19) is especially severe in aged populations1. Vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are highly effective, but vaccine efficacy is partly compromised by the emergence of SARS-CoV-2 variants with enhanced transmissibility2. The emergence of these variants emphasizes the need for further development of anti-SARS-CoV-2 therapies, especially for aged populations. Here we describe the isolation of highly virulent mouse-adapted viruses and use them to test a new therapeutic drug in infected aged animals. Many of the alterations observed in SARS-CoV-2 during mouse adaptation (positions 417, 484, 493, 498 and 501 of the spike protein) also arise in humans in variants of concern2. Their appearance during mouse adaptation indicates that immune pressure is not required for selection. For murine SARS, for which severity is also age dependent, elevated levels of an eicosanoid (prostaglandin D2 (PGD2)) and a phospholipase (phospholipase A2 group 2D (PLA2G2D)) contributed to poor outcomes in aged mice3,4. mRNA expression of PLA2G2D and prostaglandin D2 receptor (PTGDR), and production of PGD2 also increase with ageing and after SARS-CoV-2 infection in dendritic cells derived from human peripheral blood mononuclear cells. Using our mouse-adapted SARS-CoV-2, we show that middle-aged mice lacking expression of PTGDR or PLA2G2D are protected from severe disease. Furthermore, treatment with a PTGDR antagonist, asapiprant, protected aged mice from lethal infection. PTGDR antagonism is one of the first interventions in SARS-CoV-2-infected animals that specifically protects aged animals, suggesting that the PLA2G2D-PGD2/PTGDR pathway is a useful target for therapeutic interventions.


Subject(s)
COVID-19 , SARS-CoV-2 , Animals , Eicosanoids , Leukocytes, Mononuclear , Mice , Organic Chemicals , Oxazoles , Piperazines , Polyesters , Prostaglandins , Spike Glycoprotein, Coronavirus , Sulfonamides
2.
J Int Assoc Provid AIDS Care ; 21: 23259582221084543, 2022.
Article in English | MEDLINE | ID: covidwho-1794048

ABSTRACT

Background: Adherence to antiretroviral therapy (ART) is the key determinant of virological suppression in people living with HIV (PLHIV). This study reports factors associated with non-adherence among PLHIV one year after introducing dolutegravir (DTG) based regimens in Tanzania. Methods: A hospital-based cross-sectional study was conducted in two health facilities in Dar es Salaam, Tanzania, in 2020. Results: A total of 406 PLHIV were recruited, where the majority (73.4%) were females, with 94.6% of patients being on DTG based regimens. Factors such as refill interval and sharing of antiretrovirals had significant effects on adherence. Multivariate analysis found that patients attending care and treatment center (CTC) at Temeke Regional Referral Hospital (RRH) were 4.3 times more likely to have non-adherence compared to those attending Amana RRH (aOR [adjusted odds ratio] 4.3, 95% CI [confidence interval]: 2.38 - 7.91, p-value < 0.0001). Conclusions: Sustainable adherence counseling is warranted to overcome non-adherence to ART.


Subject(s)
HIV Infections , Anti-Retroviral Agents/therapeutic use , Cross-Sectional Studies , Female , HIV Infections/psychology , Heterocyclic Compounds, 3-Ring , Humans , Male , Oxazines , Piperazines , Pyridones , Tanzania/epidemiology
3.
Front Public Health ; 10: 819052, 2022.
Article in English | MEDLINE | ID: covidwho-1785438

ABSTRACT

Aims: Our study aimed to develop a two-factor self-administered orthogonal questionnaire to assess the experience of perceived physical inactivity, to test its psychometric properties, to confirm its relationships with fear of COVID-19, and finally, with perceived stress during the pandemic. Methods: A total of 481 Tunisian subjects collected in several cities, aged from 16 to 67 years with a mean age = 32.48 ± 9.46, and of both sexes participate in our study with (male: 51.8%) and (female: 48.2%), divided according to the level of study into three categories. All subjects voluntarily answered the PIPES questionnaire, the IPAQ scale, the COVID-19 fear scale and the PSS-10 test. Results: The results of the exploratory and confirmatory factor analysis supported the robustness of the tool measure. In addition, examination of configurational, metric, scalar, and strict invariance supported the equivalence of the structure by gender and educational level. Concurrent validity was established by the positive association of a negative perception of physical inactivity with scores measured by the IPAQ scale and a negative association with scores of COVID-19 fear and perceived stress. Whereas, a positive perception of physical inactivity from the COVID-19 scale was negatively associated with the IPAQ and positively associated with fear of COVID-19 and perceived stress. Conclusion: The PIPES-10 scale can be used to measure the perception of physical inactivity in different situations.


Subject(s)
COVID-19 , Adult , Alkanesulfonic Acids , COVID-19/epidemiology , Female , Humans , Male , Pandemics , Pilot Projects , Piperazines , Psychometrics , Sedentary Behavior , Young Adult
4.
J Int AIDS Soc ; 25(3): e25885, 2022 03.
Article in English | MEDLINE | ID: covidwho-1729149

ABSTRACT

INTRODUCTION: In December 2019, dolutegravir-based treatment was recommended as first-line antiretroviral therapy (ART) in South Africa. Dolutegravir has clinically significant interactions with several commonly used drugs, such as rifampicin, metformin and cation-containing medicines. National guidelines detail these interactions and how to manage them. While previous international studies have shown low healthcare worker knowledge of drug-drug interactions, there is a paucity of information on antiretroviral interaction knowledge in the South African setting, where much ART is nurse-led. The study aimed to determine this knowledge and to describe which variables were associated with gaps in knowledge. METHODS: An anonymous online survey of healthcare workers in the field of HIV was conducted in August/September 2020. The survey was designed, tested and piloted, and included sections on demographics, guideline access and training, interaction knowledge, counselling and the effect of COVID-19. Dissemination was via e-mail and social media (convenience sampling). Descriptive and inferential analysis was done using proportions and the 95% confidence interval to determine relationships between independent and dependent variables. Research ethics approval was obtained from the University of Cape Town's Human Research Ethics Committee (HREC Ref: 357/2020). RESULTS AND DISCUSSION: In total, 1950 survey responses were included in the analysis - 47.1% nurses, 35.8% doctors and 8.9% pharmacists. When asked whether they were aware that dolutegravir has interactions, 70% said yes, 13.9% said no and 16.1% did not answer. Knowledge of specific interactions and the dosing changes needed was low with a wide range between different drugs: 79.7% knew to double the dolutegravir dose with rifampicin, but with calcium, 5.1% picked both correct dosing options and 33.7% picked one of the two correct options. Access to guidelines and training were positively associated with drug interaction knowledge. CONCLUSIONS: There are gaps in the awareness and knowledge of dolutegravir interactions and how to adjust dosing among South African healthcare workers.


Subject(s)
COVID-19 , HIV Infections , Cross-Sectional Studies , Drug Interactions , HIV Infections/drug therapy , Health Knowledge, Attitudes, Practice , Health Personnel , Heterocyclic Compounds, 3-Ring , Humans , Oxazines , Piperazines , Pyridones , SARS-CoV-2 , South Africa
5.
Mar Drugs ; 20(3)2022 Feb 24.
Article in English | MEDLINE | ID: covidwho-1725847

ABSTRACT

The COVID-19 pandemic and its continuing emerging variants emphasize the need to discover appropriate treatment, where vaccines alone have failed to show complete protection against the new variants of the virus. Therefore, treatment of the infected cases is critical. This paper discusses the bio-guided isolation of three indole diketopiperazine alkaloids, neoechinulin A (1), echinulin (2), and eurocristatine (3), from the Red Sea-derived Aspergillus fumigatus MR2012. Neoechinulin A (1) exhibited a potent inhibitory effect against SARS-CoV-2 Mpro with IC50 value of 0.47 µM, which is comparable to the reference standard GC376. Despite the structural similarity between the three compounds, only 1 showed a promising effect. The mechanism of inhibition is discussed in light of a series of extensive molecular docking, classical and steered molecular dynamics simulation experiments. This paper sheds light on indole diketopiperazine alkaloids as a potential structural motif against SARS-CoV-2 Mpro. Additionally, it highlights the potential of different molecular docking and molecular dynamics simulation approaches in the discrimination between active and inactive structurally related Mpro inhibitors.


Subject(s)
Antiviral Agents/chemistry , Coronavirus 3C Proteases/antagonists & inhibitors , Cysteine Proteinase Inhibitors/chemistry , Indole Alkaloids/chemistry , Piperazines/chemistry , SARS-CoV-2/enzymology , Alkaloids/chemistry , Alkaloids/isolation & purification , Antiviral Agents/isolation & purification , Aspergillus fumigatus/chemistry , Cysteine Proteinase Inhibitors/isolation & purification , Indole Alkaloids/isolation & purification , Molecular Docking Simulation , Molecular Dynamics Simulation , Piperazines/isolation & purification
6.
J Virol ; 95(24): e0139921, 2021 11 23.
Article in English | MEDLINE | ID: covidwho-1691426

ABSTRACT

Targeting host factors is a promising strategy to develop broad-spectrum antiviral drugs. Drugs targeting anti-apoptotic Bcl-2 family proteins that were originally developed as tumor suppressors have been reported to inhibit multiplication of different types of viruses. However, the mechanisms whereby Bcl-2 inhibitors exert their antiviral activity remain poorly understood. In this study, we have investigated the mechanisms by which obatoclax (OLX) and ABT-737 Bcl-2 inhibitors exhibited a potent antiviral activity against the mammarenavirus lymphocytic choriomeningitis virus (LCMV). OLX and ABT-737 potent anti-LCMV activity was not associated with their proapoptotic properties but rather with their ability to induce cell arrest at the G0/G1 phase. OLX- and ABT-737-mediated inhibition of Bcl-2 correlated with reduced expression levels of thymidine kinase 1 (TK1), cyclin A2 (CCNA2), and cyclin B1 (CCNB1) cell cycle regulators. In addition, small interfering RNA (siRNA)-mediated knockdown of TK1, CCNA2, and CCNB1 resulted in reduced levels of LCMV multiplication. The antiviral activity exerted by Bcl-2 inhibitors correlated with reduced levels of viral RNA synthesis at early times of infection. Importantly, ABT-737 exhibited moderate efficacy in a mouse model of LCMV infection, and Bcl-2 inhibitors displayed broad-spectrum antiviral activities against different mammarenaviruses and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Our results suggest that Bcl-2 inhibitors, actively being explored as anticancer therapeutics, might be repositioned as broad-spectrum antivirals. IMPORTANCE Antiapoptotic Bcl-2 inhibitors have been shown to exert potent antiviral activities against various types of viruses via mechanisms that are currently poorly understood. This study has revealed that Bcl-2 inhibitors' mediation of cell cycle arrest at the G0/G1 phase, rather than their proapoptotic activity, plays a critical role in blocking mammarenavirus multiplication in cultured cells. In addition, we show that Bcl-2 inhibitor ABT-737 exhibited moderate antimammarenavirus activity in vivo and that Bcl-2 inhibitors displayed broad-spectrum antiviral activities against different mammarenaviruses and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Our results suggest that Bcl-2 inhibitors, actively being explored as anticancer therapeutics, might be repositioned as broad-spectrum antivirals.


Subject(s)
Apoptosis , Arenaviridae/drug effects , COVID-19/drug therapy , Proto-Oncogene Proteins c-bcl-2/metabolism , A549 Cells , Animals , Antiviral Agents/pharmacology , Apoptosis Regulatory Proteins/pharmacology , Biphenyl Compounds/pharmacology , COVID-19/virology , Cell Cycle , Cell Cycle Checkpoints/drug effects , Cells, Cultured/drug effects , Cells, Cultured/virology , Chlorocebus aethiops , Cyclin A2/biosynthesis , Cyclin B1/biosynthesis , G1 Phase , Humans , Indoles/pharmacology , Mice , Mice, Inbred C57BL , Nitrophenols/pharmacology , Piperazines/pharmacology , Pyrroles/pharmacology , Resting Phase, Cell Cycle , SARS-CoV-2 , Sulfonamides/pharmacology , Thymidine Kinase/biosynthesis , Vero Cells
7.
Sci Adv ; 8(5): eabl8920, 2022 02 04.
Article in English | MEDLINE | ID: covidwho-1673337

ABSTRACT

Dexamethasone is widely used as an immunosuppressive therapy and recently as COVID-19 treatment. Here, we demonstrate that dexamethasone sensitizes to ferroptosis, a form of iron-catalyzed necrosis, previously suggested to contribute to diseases such as acute kidney injury, myocardial infarction, and stroke, all of which are triggered by glutathione (GSH) depletion. GSH levels were significantly decreased by dexamethasone. Mechanistically, we identified that dexamethasone up-regulated the GSH metabolism regulating protein dipeptidase-1 (DPEP1) in a glucocorticoid receptor (GR)-dependent manner. DPEP1 knockdown reversed the phenotype of dexamethasone-induced ferroptosis sensitization. Ferroptosis inhibitors, the DPEP1 inhibitor cilastatin, or genetic DPEP1 inactivation reversed the dexamethasone-induced increase in tubular necrosis in freshly isolated renal tubules. Our data indicate that dexamethasone sensitizes to ferroptosis by a GR-mediated increase in DPEP1 expression and GSH depletion. Together, we identified a previously unknown mechanism of glucocorticoid-mediated sensitization to ferroptosis bearing clinical and therapeutic implications.


Subject(s)
Dexamethasone/pharmacology , Dipeptidases/genetics , Ferroptosis/drug effects , Ferroptosis/genetics , Gene Expression Regulation/drug effects , Glutathione/metabolism , Receptors, Glucocorticoid/metabolism , Carbolines/adverse effects , Carbolines/pharmacology , Cell Line , Dipeptidases/metabolism , Fluorescent Antibody Technique , GPI-Linked Proteins/genetics , GPI-Linked Proteins/metabolism , Gene Knockdown Techniques , Humans , Immunophenotyping , Oxidation-Reduction/drug effects , Piperazines/adverse effects , Piperazines/pharmacology
8.
J Nat Prod ; 85(1): 284-291, 2022 01 28.
Article in English | MEDLINE | ID: covidwho-1596477

ABSTRACT

We have previously reported that neoechinulin B (1a), a prenylated indole diketopiperazine alkaloid, shows antiviral activities against hepatitis C virus (HCV) via the inactivation of the liver X receptors (LXRs) and the resultant disruption of double-membrane vesicles. In this study, a two-step synthesis of the diketopiperazine scaffold of 1a was achieved by the base-induced coupling of 1,4-diacetyl-3-{[(tert-butyldimethylsilyl)oxy]methyl}piperazine-2,5-dione with aldehydes, followed by the treatment of the resultant coupling products with tetra-n-butylammonium fluoride. Compound 1a and its 16 derivatives 1b-q were prepared using this method. Furthermore, variecolorin H, a related alkaloid, was obtained by the acid treatment of 1a in MeOH. The antiviral evaluation of 1a and its derivatives revealed that 1a, 1c, 1d, 1h, 1j, 1l, and 1o exhibited both anti-HCV and anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) activities. The results of this study indicate that the exomethylene moiety on the diketopiperazine ring is important for the antiviral activities. The antiviral compounds can inhibit the production of HCV and SARS-CoV-2 by inactivating LXRs.


Subject(s)
Alkaloids/pharmacology , Antiviral Agents/pharmacology , Hepacivirus/drug effects , Piperazines/pharmacology , SARS-CoV-2/drug effects , Alkaloids/chemical synthesis , Alkaloids/chemistry , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Cell Line, Tumor , Diketopiperazines/chemistry , Diketopiperazines/pharmacology , Humans , Liver X Receptors/antagonists & inhibitors , Molecular Structure , Piperazines/chemical synthesis , Piperazines/chemistry , Structure-Activity Relationship , Transcription, Genetic/drug effects
9.
J Med Virol ; 93(12): 6557-6565, 2021 12.
Article in English | MEDLINE | ID: covidwho-1544300

ABSTRACT

The purpose of this study was to compare the effectiveness of Atazanavir/Ritonavir/Dolutegravir/Hydroxychloroquine and Lopinavir/Ritonavir/Hydroxychloroquine treatment regimens in COVID-19 patients based on clinical and laboratory parameters. We prospectively evaluated the clinical and laboratory outcomes of 62 moderate to severe COVID-19 patients during a 10-day treatment plan. Patients were randomly assigned to either KH (receiving Lopinavir/Ritonavir [Kaletra] plus Hydroxychloroquine) or ADH (receiving Atazanavir/Ritonavir, Dolutegravir, and Hydroxychloroquine) groups. During this period, clinical and laboratory parameters and outcomes such as intensive care unit (ICU) admission or mortality rate were recorded. Compared to the KH group, after the treatment period, patients in the ADH group had higher activated partial thromboplastin time (aPTT) (12, [95% confidence interval [CI]: 6.97, 17.06), p = <0.01), international normalized ratio (INR) (0.17, [95% CI: 0.07, 0.27), p = <0.01) and lower C-reactive protein (CRP) (-14.29, (95% CI: -26.87, -1.71), p = 0.03) and potassium (-0.53, (95% CI: -1.03, -0.03), p = 0.04) values. Moreover, a higher number of patients in the KH group needed invasive ventilation (6 (20%) vs. 1 (3.1%), p = 0.05) and antibiotic administration (27 (90%) vs. 21(65.6), p = 0.02) during hospitalization while patients in the ADH group needed more corticosteroid administration (9 (28.1%) vs. 2 (6.7%), p = 0.03). There was no difference in mortality rate, ICU admission rate, and hospitalization period between the study groups. Our results suggest that the Atazanavir/Dolutegravir treatment regimen may result in a less severe disease course compared to the Lopinavir/Ritonavir treatment regimen and can be considered as an alternative treatment option beside standard care. However, to confirm our results, larger-scale studies are recommended.


Subject(s)
Antiviral Agents/therapeutic use , Atazanavir Sulfate/therapeutic use , COVID-19/drug therapy , Heterocyclic Compounds, 3-Ring/therapeutic use , Hydroxychloroquine/therapeutic use , Lopinavir/therapeutic use , Oxazines/therapeutic use , Piperazines/therapeutic use , Pyridones/therapeutic use , Ritonavir/therapeutic use , Antiviral Agents/administration & dosage , Atazanavir Sulfate/administration & dosage , COVID-19/pathology , Drug Combinations , Drug Therapy, Combination , Female , Heterocyclic Compounds, 3-Ring/administration & dosage , Humans , Hydroxychloroquine/administration & dosage , Lopinavir/administration & dosage , Male , Middle Aged , Oxazines/administration & dosage , Piperazines/administration & dosage , Pyridones/administration & dosage , Ritonavir/administration & dosage , Treatment Outcome
10.
J Chem Inf Model ; 62(1): 116-128, 2022 01 10.
Article in English | MEDLINE | ID: covidwho-1521685

ABSTRACT

Despite the recent availability of vaccines against the acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the search for inhibitory therapeutic agents has assumed importance especially in the context of emerging new viral variants. In this paper, we describe the discovery of a novel noncovalent small-molecule inhibitor, MCULE-5948770040, that binds to and inhibits the SARS-Cov-2 main protease (Mpro) by employing a scalable high-throughput virtual screening (HTVS) framework and a targeted compound library of over 6.5 million molecules that could be readily ordered and purchased. Our HTVS framework leverages the U.S. supercomputing infrastructure achieving nearly 91% resource utilization and nearly 126 million docking calculations per hour. Downstream biochemical assays validate this Mpro inhibitor with an inhibition constant (Ki) of 2.9 µM (95% CI 2.2, 4.0). Furthermore, using room-temperature X-ray crystallography, we show that MCULE-5948770040 binds to a cleft in the primary binding site of Mpro forming stable hydrogen bond and hydrophobic interactions. We then used multiple µs-time scale molecular dynamics (MD) simulations and machine learning (ML) techniques to elucidate how the bound ligand alters the conformational states accessed by Mpro, involving motions both proximal and distal to the binding site. Together, our results demonstrate how MCULE-5948770040 inhibits Mpro and offers a springboard for further therapeutic design.


Subject(s)
COVID-19 , Protease Inhibitors , Antiviral Agents , Coronavirus 3C Proteases , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , Orotic Acid/analogs & derivatives , Piperazines , SARS-CoV-2
11.
J Med Chem ; 64(23): 17366-17383, 2021 12 09.
Article in English | MEDLINE | ID: covidwho-1493002

ABSTRACT

Creating small-molecule antivirals specific for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) proteins is crucial to battle coronavirus disease 2019 (COVID-19). SARS-CoV-2 main protease (Mpro) is an established drug target for the design of protease inhibitors. We performed a structure-activity relationship (SAR) study of noncovalent compounds that bind in the enzyme's substrate-binding subsites S1 and S2, revealing structural, electronic, and electrostatic determinants of these sites. The study was guided by the X-ray/neutron structure of Mpro complexed with Mcule-5948770040 (compound 1), in which protonation states were directly visualized. Virtual reality-assisted structure analysis and small-molecule building were employed to generate analogues of 1. In vitro enzyme inhibition assays and room-temperature X-ray structures demonstrated the effect of chemical modifications on Mpro inhibition, showing that (1) maintaining correct geometry of an inhibitor's P1 group is essential to preserve the hydrogen bond with the protonated His163; (2) a positively charged linker is preferred; and (3) subsite S2 prefers nonbulky modestly electronegative groups.


Subject(s)
Coronavirus 3C Proteases , Protease Inhibitors , Orotic Acid/analogs & derivatives , Piperazines , Protein Conformation , Static Electricity
12.
Afr J Prim Health Care Fam Med ; 13(1): e1-e3, 2021 Sep 30.
Article in English | MEDLINE | ID: covidwho-1463908

ABSTRACT

A group of Vanguard Community Health Centre doctors embarked on a Health System's Improvement (HSI) project with the aim of reducing harm to renal function in patients who were either commenced on or switched to a dolutegravir (DTG)-based antiretroviral therapy (ART) regimen since 2019, when the usual monitoring and evaluation of ART-regimen switches were disrupted by the coronavirus disease 2019 (COVID-19) pandemic. This intended harm-reduction exercise, involving a reflective process that was facilitated by the family physician, led to the development of a Vanguard Renal Protection Surveillance tool, which is now used at Vanguard to detect and prevent renal decline.


Subject(s)
COVID-19 , HIV Infections , HIV Infections/drug therapy , Heterocyclic Compounds, 3-Ring , Humans , Kidney/physiology , Oxazines , Physicians, Family , Piperazines , Pyridones , SARS-CoV-2
13.
J Virol ; 95(24): e0139921, 2021 11 23.
Article in English | MEDLINE | ID: covidwho-1443355

ABSTRACT

Targeting host factors is a promising strategy to develop broad-spectrum antiviral drugs. Drugs targeting anti-apoptotic Bcl-2 family proteins that were originally developed as tumor suppressors have been reported to inhibit multiplication of different types of viruses. However, the mechanisms whereby Bcl-2 inhibitors exert their antiviral activity remain poorly understood. In this study, we have investigated the mechanisms by which obatoclax (OLX) and ABT-737 Bcl-2 inhibitors exhibited a potent antiviral activity against the mammarenavirus lymphocytic choriomeningitis virus (LCMV). OLX and ABT-737 potent anti-LCMV activity was not associated with their proapoptotic properties but rather with their ability to induce cell arrest at the G0/G1 phase. OLX- and ABT-737-mediated inhibition of Bcl-2 correlated with reduced expression levels of thymidine kinase 1 (TK1), cyclin A2 (CCNA2), and cyclin B1 (CCNB1) cell cycle regulators. In addition, small interfering RNA (siRNA)-mediated knockdown of TK1, CCNA2, and CCNB1 resulted in reduced levels of LCMV multiplication. The antiviral activity exerted by Bcl-2 inhibitors correlated with reduced levels of viral RNA synthesis at early times of infection. Importantly, ABT-737 exhibited moderate efficacy in a mouse model of LCMV infection, and Bcl-2 inhibitors displayed broad-spectrum antiviral activities against different mammarenaviruses and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Our results suggest that Bcl-2 inhibitors, actively being explored as anticancer therapeutics, might be repositioned as broad-spectrum antivirals. IMPORTANCE Antiapoptotic Bcl-2 inhibitors have been shown to exert potent antiviral activities against various types of viruses via mechanisms that are currently poorly understood. This study has revealed that Bcl-2 inhibitors' mediation of cell cycle arrest at the G0/G1 phase, rather than their proapoptotic activity, plays a critical role in blocking mammarenavirus multiplication in cultured cells. In addition, we show that Bcl-2 inhibitor ABT-737 exhibited moderate antimammarenavirus activity in vivo and that Bcl-2 inhibitors displayed broad-spectrum antiviral activities against different mammarenaviruses and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Our results suggest that Bcl-2 inhibitors, actively being explored as anticancer therapeutics, might be repositioned as broad-spectrum antivirals.


Subject(s)
Apoptosis , Arenaviridae/drug effects , COVID-19/drug therapy , Proto-Oncogene Proteins c-bcl-2/metabolism , A549 Cells , Animals , Antiviral Agents/pharmacology , Apoptosis Regulatory Proteins/pharmacology , Biphenyl Compounds/pharmacology , COVID-19/virology , Cell Cycle , Cell Cycle Checkpoints/drug effects , Cells, Cultured/drug effects , Cells, Cultured/virology , Chlorocebus aethiops , Cyclin A2/biosynthesis , Cyclin B1/biosynthesis , G1 Phase , Humans , Indoles/pharmacology , Mice , Mice, Inbred C57BL , Nitrophenols/pharmacology , Piperazines/pharmacology , Pyrroles/pharmacology , Resting Phase, Cell Cycle , SARS-CoV-2 , Sulfonamides/pharmacology , Thymidine Kinase/biosynthesis , Vero Cells
14.
Nursing ; 51(10): 18-29, 2021 Oct 01.
Article in English | MEDLINE | ID: covidwho-1440656

ABSTRACT

ABSTRACT: The second of a two-part series, this article describes eight recently approved drugs, including the first drug approved for the treatment of SARS-CoV-2, a first-in-class HIV attachment inhibitor, and a new intravenous injection indicated for the treatment of acute pain in adults for whom other treatments are ineffective.


Subject(s)
Drug Approval , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/therapeutic use , Alanine/analogs & derivatives , Alanine/therapeutic use , Amisulpride/therapeutic use , COVID-19/drug therapy , Carbamates/therapeutic use , Cephalosporins/therapeutic use , Chlorophenols/therapeutic use , Drug Combinations , Fumarates/therapeutic use , Humans , Indans/therapeutic use , Organophosphates/therapeutic use , Oxadiazoles/therapeutic use , Piperazines/therapeutic use , Spiro Compounds/therapeutic use , Tetrazoles/therapeutic use , Thiophenes/therapeutic use , Tromethamine/therapeutic use , United States , United States Food and Drug Administration
15.
ACS Chem Biol ; 16(4): 642-650, 2021 04 16.
Article in English | MEDLINE | ID: covidwho-1387141

ABSTRACT

Host-cell cysteine proteases play an essential role in the processing of the viral spike protein of SARS coronaviruses. K777, an irreversible, covalent inactivator of cysteine proteases that has recently completed phase 1 clinical trials, reduced SARS-CoV-2 viral infectivity in several host cells: Vero E6 (EC50< 74 nM), HeLa/ACE2 (4 nM), Caco-2 (EC90 = 4.3 µM), and A549/ACE2 (<80 nM). Infectivity of Calu-3 cells depended on the cell line assayed. If Calu-3/2B4 was used, EC50 was 7 nM, but in the ATCC Calu-3 cell line without ACE2 enrichment, EC50 was >10 µM. There was no toxicity to any of the host cell lines at 10-100 µM K777 concentration. Kinetic analysis confirmed that K777 was a potent inhibitor of human cathepsin L, whereas no inhibition of the SARS-CoV-2 cysteine proteases (papain-like and 3CL-like protease) was observed. Treatment of Vero E6 cells with a propargyl derivative of K777 as an activity-based probe identified human cathepsin B and cathepsin L as the intracellular targets of this molecule in both infected and uninfected Vero E6 cells. However, cleavage of the SARS-CoV-2 spike protein was only carried out by cathepsin L. This cleavage was blocked by K777 and occurred in the S1 domain of the SARS-CoV-2 spike protein, a different site from that previously observed for the SARS-CoV-1 spike protein. These data support the hypothesis that the antiviral activity of K777 is mediated through inhibition of the activity of host cathepsin L and subsequent loss of cathepsin L-mediated viral spike protein processing.


Subject(s)
Antiviral Agents/pharmacology , Cysteine Proteinase Inhibitors/pharmacology , Phenylalanine/pharmacology , Piperazines/pharmacology , SARS-CoV-2/drug effects , Tosyl Compounds/pharmacology , Animals , Cathepsin L/antagonists & inhibitors , Cathepsin L/metabolism , Cell Line, Tumor , Chlorocebus aethiops , Humans , Microbial Sensitivity Tests , Protein Domains , Proteolysis , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/metabolism , Vero Cells , Virus Internalization/drug effects
16.
J Virol ; 95(17): e0079421, 2021 08 10.
Article in English | MEDLINE | ID: covidwho-1350003

ABSTRACT

Increased mortality in COVID-19 cases is often associated with microvascular complications. We have recently shown that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein promotes an inflammatory cytokine interleukin 6 (IL-6)/IL-6R-induced trans signaling response and alarmin secretion. Virus-infected or spike-transfected human epithelial cells exhibited an increase in senescence, with a release of senescence-associated secretory phenotype (SASP)-related inflammatory molecules. Introduction of the bromodomain-containing protein 4 (BRD4) inhibitor AZD5153 to senescent epithelial cells reversed this effect and reduced SASP-related inflammatory molecule release in TMNK-1 or EAhy926 (representative human endothelial cell lines), when cells were exposed to cell culture medium (CM) derived from A549 cells expressing SARS-CoV-2 spike protein. Cells also exhibited a senescence phenotype with enhanced p16, p21, and senescence-associated ß-galactosidase (SA-ß-Gal) expression and triggered SASP pathways. Inhibition of IL-6 trans signaling by tocilizumab and inhibition of inflammatory receptor signaling by the Bruton's tyrosine kinase (BTK) inhibitor zanubrutinib, prior to exposure of CM to endothelial cells, inhibited p21 and p16 induction. We also observed an increase in reactive oxygen species (ROS) in A549 spike-transfected and endothelial cells exposed to spike-transfected CM. ROS generation in endothelial cell lines was reduced after treatment with tocilizumab and zanubrutinib. Cellular senescence was associated with an increased level of the endothelial adhesion molecules vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1), which have in vitro leukocyte attachment potential. Inhibition of senescence or SASP function prevented VCAM-1/ICAM-1 expression and leukocyte attachment. Taken together, we identified that human endothelial cells exposed to cell culture supernatant derived from SARS-CoV-2 spike protein expression displayed cellular senescence markers, leading to enhanced leukocyte adhesion. IMPORTANCE The present study was aimed at examining the underlying mechanism of extrapulmonary manifestations of SARS-CoV-2 spike protein-associated pathogenesis, with the notion that infection of the pulmonary epithelium can lead to mediators that drive endothelial dysfunction. We utilized SARS-CoV-2 spike protein expression in cultured human hepatocytes (Huh7.5) and pneumocytes (A549) to generate conditioned culture medium (CM). Endothelial cell lines (TMNK-1 or EAhy926) treated with CM exhibited an increase in cellular senescence markers by a paracrine mode and led to leukocyte adhesion. Overall, the link between these responses in endothelial cell senescence and a potential contribution to microvascular complication in productively SARS-CoV-2-infected humans is implicated. Furthermore, the use of inhibitors (BTK, IL-6, and BRD4) showed a reverse effect in the senescent cells. These results may support the selection of potential adjunct therapeutic modalities to impede SARS-CoV-2-associated pathogenesis.


Subject(s)
Cellular Senescence , Endothelial Cells/metabolism , Leukocytes/metabolism , Paracrine Communication , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/metabolism , A549 Cells , Cell Adhesion , Cell Cycle Proteins/antagonists & inhibitors , Cell Cycle Proteins/metabolism , Endothelial Cells/pathology , Endothelial Cells/virology , Heterocyclic Compounds, 2-Ring/pharmacology , Humans , Intercellular Adhesion Molecule-1/metabolism , Interleukin-6/metabolism , Leukocytes/pathology , Leukocytes/virology , Piperazines/pharmacology , Pyrazoles , Pyridazines , Reactive Oxygen Species/metabolism , Receptors, Interleukin-6/metabolism , Signal Transduction , Transcription Factors/antagonists & inhibitors , Transcription Factors/metabolism , Vascular Cell Adhesion Molecule-1/metabolism
17.
Curr Opin Chem Biol ; 65: 74-84, 2021 12.
Article in English | MEDLINE | ID: covidwho-1312961

ABSTRACT

Drug repurposing aims to find new uses for already existing and approved drugs. We now provide a brief overview of recent developments in drug repurposing using machine learning alongside other computational approaches for comparison. We also highlight several applications for cancer using kinase inhibitors, Alzheimer's disease as well as COVID-19.


Subject(s)
Alzheimer Disease/drug therapy , COVID-19/drug therapy , Drug Repositioning/trends , Machine Learning , Neoplasms/drug therapy , Antineoplastic Agents/therapeutic use , Antiviral Agents/therapeutic use , Clemastine/pharmacology , Computational Biology/methods , Dipyridamole/pharmacology , Humans , Hydroxychloroquine/pharmacology , Lenalidomide/pharmacology , Neuroprotective Agents/therapeutic use , Piperazines/pharmacology , Piperidines/pharmacology , Protein Kinase Inhibitors/pharmacology
18.
J Med Virol ; 93(12): 6557-6565, 2021 12.
Article in English | MEDLINE | ID: covidwho-1306657

ABSTRACT

The purpose of this study was to compare the effectiveness of Atazanavir/Ritonavir/Dolutegravir/Hydroxychloroquine and Lopinavir/Ritonavir/Hydroxychloroquine treatment regimens in COVID-19 patients based on clinical and laboratory parameters. We prospectively evaluated the clinical and laboratory outcomes of 62 moderate to severe COVID-19 patients during a 10-day treatment plan. Patients were randomly assigned to either KH (receiving Lopinavir/Ritonavir [Kaletra] plus Hydroxychloroquine) or ADH (receiving Atazanavir/Ritonavir, Dolutegravir, and Hydroxychloroquine) groups. During this period, clinical and laboratory parameters and outcomes such as intensive care unit (ICU) admission or mortality rate were recorded. Compared to the KH group, after the treatment period, patients in the ADH group had higher activated partial thromboplastin time (aPTT) (12, [95% confidence interval [CI]: 6.97, 17.06), p = <0.01), international normalized ratio (INR) (0.17, [95% CI: 0.07, 0.27), p = <0.01) and lower C-reactive protein (CRP) (-14.29, (95% CI: -26.87, -1.71), p = 0.03) and potassium (-0.53, (95% CI: -1.03, -0.03), p = 0.04) values. Moreover, a higher number of patients in the KH group needed invasive ventilation (6 (20%) vs. 1 (3.1%), p = 0.05) and antibiotic administration (27 (90%) vs. 21(65.6), p = 0.02) during hospitalization while patients in the ADH group needed more corticosteroid administration (9 (28.1%) vs. 2 (6.7%), p = 0.03). There was no difference in mortality rate, ICU admission rate, and hospitalization period between the study groups. Our results suggest that the Atazanavir/Dolutegravir treatment regimen may result in a less severe disease course compared to the Lopinavir/Ritonavir treatment regimen and can be considered as an alternative treatment option beside standard care. However, to confirm our results, larger-scale studies are recommended.


Subject(s)
Antiviral Agents/therapeutic use , Atazanavir Sulfate/therapeutic use , COVID-19/drug therapy , Heterocyclic Compounds, 3-Ring/therapeutic use , Hydroxychloroquine/therapeutic use , Lopinavir/therapeutic use , Oxazines/therapeutic use , Piperazines/therapeutic use , Pyridones/therapeutic use , Ritonavir/therapeutic use , Antiviral Agents/administration & dosage , Atazanavir Sulfate/administration & dosage , COVID-19/pathology , Drug Combinations , Drug Therapy, Combination , Female , Heterocyclic Compounds, 3-Ring/administration & dosage , Humans , Hydroxychloroquine/administration & dosage , Lopinavir/administration & dosage , Male , Middle Aged , Oxazines/administration & dosage , Piperazines/administration & dosage , Pyridones/administration & dosage , Ritonavir/administration & dosage , Treatment Outcome
19.
Adv Ther ; 38(6): 3223-3265, 2021 06.
Article in English | MEDLINE | ID: covidwho-1279500

ABSTRACT

INTRODUCTION: Centhaquine (Lyfaquin®) showed significant efficacy as a resuscitative agent in animal models of haemorrhagic shock. Its safety and tolerability were confirmed in healthy human volunteers. In this study, our primary objective was to determine the safety, and the secondary objective was to assess the efficacy of centhaquine in patients with hypovolemic shock. METHODS: A prospective, multicentre, randomized phase II study was conducted in male and female patients aged 18-70 years with hypovolemic shock having systolic BP ≤ 90 mmHg. Patients were randomized in a 1:1 ratio to either the control or centhaquine group. The control group received 100 ml of normal saline infusion over 1 h, while the centhaquine group received 0.01 mg/kg of centhaquine in 100 ml normal saline infusion over 1 h. Every patient received standard of care (SOC) and was followed for 28 days. RESULTS: Fifty patients were included, and 45 completed the trial: 22 in the control group and 23 in the centhaquine group. The demographics of patients in both groups were comparable. No adverse event related to centhaquine was recorded in the 28-day observation period. The baseline, Injury Scoring System score, haemoglobin, and haematocrit were similar in both groups. However, 91% of the patients in the centhaquine group needed major surgery, whereas only 68% in the control group (p = 0.0526). Twenty-eight-day all-cause mortality was 0/23 in the centhaquine group and 2/22 in the control group. The percent time in ICU and ventilator support was less in the centhaquine group than in the control group. The total amount of vasopressors needed in the first 48 h of resuscitation was lower in the centhaquine group than in the control group (3.12 ± 2.18 vs. 9.39 ± 4.28 mg). An increase in systolic and diastolic BP from baseline through 48 h was more marked in the centhaquine group than in the control group. Compared with the control group, blood lactate level was lower by 1.75 ± 1.07 mmol/l in the centhaquine group on day 3 of resuscitation. Improvements in base deficit, multiple organ dysfunction syndrome (MODS) score and adult respiratory distress syndrome (ARDS) were greater in the centhaquine group than in the control group. CONCLUSION: When added to SOC, centhaquine is a well-tolerated and effective resuscitative agent. It improves the clinical outcome of patients with hypovolemic shock. TRIAL REGISTRATION: ClinicalTrials.gov identifier number: NCT04056065.


Subject(s)
COVID-19 , Shock , Adult , Female , Humans , Male , Piperazines , Prospective Studies , SARS-CoV-2 , Shock/drug therapy
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