scholarly journals Human DDX3 protein is a valuable target to develop broad spectrum antiviral agents

2016 ◽  
Vol 113 (19) ◽  
pp. 5388-5393 ◽  
Author(s):  
Annalaura Brai ◽  
Roberta Fazi ◽  
Cristina Tintori ◽  
Claudio Zamperini ◽  
Francesca Bugli ◽  
...  
Keyword(s):  
Broad Spectrum ◽  
Antiviral Agents ◽  
Antiviral Agent ◽  
Host Factor ◽  
Human Pathogens ◽  
Genetic Barrier ◽  
Dna And Rna ◽  
Development Of Resistance ◽  
Emerging Viral Diseases ◽  
Hiv 1

Targeting a host factor essential for the replication of different viruses but not for the cells offers a higher genetic barrier to the development of resistance, may simplify therapy regimens for coinfections, and facilitates management of emerging viral diseases. DEAD-box polypeptide 3 (DDX3) is a human host factor required for the replication of several DNA and RNA viruses, including some of the most challenging human pathogens currently circulating, such as HIV-1, Hepatitis C virus, Dengue virus, and West Nile virus. Herein, we showed for the first time, to our knowledge, that the inhibition of DDX3 by a small molecule could be successfully exploited for the development of a broad spectrum antiviral agent. In addition to the multiple antiviral activities, hit compound 16d retained full activity against drug-resistant HIV-1 strains in the absence of cellular toxicity. Pharmacokinetics and toxicity studies in rats confirmed a good safety profile and bioavailability of 16d. Thus, DDX3 is here validated as a valuable therapeutic target.

scholarly journals Ivermectin as a Broad-Spectrum Host-Directed Antiviral: The Real Deal?

Cells ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 2100 ◽  
Author(s):  
David A. Jans ◽  
Kylie M. Wagstaff
Keyword(s):  
Conformational Changes ◽  
Broad Spectrum ◽  
Pseudorabies Virus ◽  
Antiviral Agent ◽  
Normal Function ◽  
Phase Iii ◽  
Parasitic Infections ◽  
Equine Encephalitis Virus ◽  
Virus West Nile ◽  
Hiv 1

The small molecule macrocyclic lactone ivermectin, approved by the US Food and Drug Administration for parasitic infections, has received renewed attention in the last eight years due to its apparent exciting potential as an antiviral. It was identified in a high-throughput chemical screen as inhibiting recognition of the nuclear localizing Human Immunodeficiency Virus-1 (HIV-1) integrase protein by the host heterodimeric importin (IMP) α/β1 complex, and has since been shown to bind directly to IMPα to induce conformational changes that prevent its normal function in mediating nuclear import of key viral and host proteins. Excitingly, cell culture experiments show robust antiviral action towards HIV-1, dengue virus (DENV), Zika virus, West Nile virus, Venezuelan equine encephalitis virus, Chikungunya virus, Pseudorabies virus, adenovirus, and SARS-CoV-2 (COVID-19). Phase III human clinical trials have been completed for DENV, with >50 trials currently in progress worldwide for SARS-CoV-2. This mini-review discusses the case for ivermectin as a host-directed broad-spectrum antiviral agent for a range of viruses, including SARS-CoV-2.

scholarly journals TMC125 Displays a High Genetic Barrier to the Development of Resistance: Evidence from In Vitro Selection Experiments

2005 ◽  
Vol 79 (20) ◽  
pp. 12773-12782 ◽  
Author(s):  
Johan Vingerhoets ◽  
Hilde Azijn ◽  
Els Fransen ◽  
Inky De Baere ◽  
Liesbet Smeulders ◽  
...  
Keyword(s):  
Wild Type Virus ◽  
Cross Resistance ◽  
Resistant Virus ◽  
Wild Type ◽  
Genetic Barrier ◽  
Development Of Resistance ◽  
Selection Experiments ◽  
The Impact ◽  
Hiv 1

ABSTRACT TMC125 is a potent new investigational nonnucleoside reverse transcriptase inhibitor (NNRTI) that is active against human immunodeficiency virus type 1 (HIV-1) with resistance to currently licensed NNRTIs. Sequential passage experiments with both wild-type virus and NNRTI-resistant virus were performed to identify mutations selected by TMC125 in vitro. In addition to “classic” selection experiments at a low multiplicity of infection (MOI) with increasing concentrations of inhibitors, experiments at a high MOI with fixed concentrations of inhibitors were performed to ensure a standardized comparison between TMC125 and current NNRTIs. Both low- and high-MOI experiments demonstrated that the development of resistance to TMC125 required multiple mutations which frequently conferred cross-resistance to efavirenz and nevirapine. In high-MOI experiments, 1 μM TMC125 completely inhibited the breakthrough of resistant virus from wild-type and NNRTI-resistant HIV-1, in contrast to efavirenz and nevirapine. Furthermore, breakthrough of virus from site-directed mutant (SDM) SDM-K103N/Y181C occurred at the same time or later with TMC125 as breakthrough from wild-type HIV-1 with efavirenz or nevirapine. The selection experiments identified mutations selected by TMC125 that included known NNRTI-associated mutations L100I, Y181C, G190E, M230L, and Y318F and the novel mutations V179I and V179F. Testing the antiviral activity of TMC125 against a panel of SDMs indicated that the impact of these individual mutations on resistance was highly dependent upon the presence and identity of coexisting mutations. These results demonstrate that TMC125 has a unique profile of activity against NNRTI-resistant virus and possesses a high genetic barrier to the development of resistance in vitro.

scholarly journals Genetic barrier to the development of resistance to rilpivirine and etravirine between HIV-1 subtypes CRF02_AG and B

2013 ◽  
Vol 68 (11) ◽  
pp. 2515-2520 ◽  
Author(s):  
D. B. Fofana ◽  
C. Soulie ◽  
A. I. Maiga ◽  
S. Fourati ◽  
I. Malet ◽  
...  
Keyword(s):  
Genetic Barrier ◽  
Development Of Resistance ◽  
Hiv 1

scholarly journals Discovery and Development of Safe-in-Man Broad-Spectrum Antiviral Agents

2019 ◽  
Author(s):  
Petter I. Andersen ◽  
Aleksandr Ianevski ◽  
Hilde Lysvand ◽  
Astra Vitkauskiene ◽  
Valentyn Oksenych ◽  
...  
Keyword(s):  
General Population ◽  
Broad Spectrum ◽  
Clinical Studies ◽  
Development Process ◽  
Antiviral Agents ◽  
Viral Diseases ◽  
The World ◽  
Key Players ◽  
Emerging Viral Diseases ◽  
Spectrum Of Indications

Viral diseases are one of the leading causes of morbidity and mortality in the world. Broad-spectrum antiviral agents (BSAAs) are key players in control of human viral diseases. Here, we reviewed the discovery and development process of BSAAs, focusing on compounds with available safety profiles in human. In addition, we summarized the information on approved, investigational and experimental safe-in-man BSAAs in freely accessible database at https://drugvirus.info/. The number of approved BSAAs will be increased as well as their spectrum of indications will be expanded pending the results of further pre-clinical and clinical studies. This will ultimately reinforce the arsenal of available antiviral options and provide better protection of general population from emerging and re-emerging viral diseases.

Genetic Barrier to the Development of Resistance to Integrase Inhibitors in HIV-1 Subtypes CRF01_AE and B

Intervirology ◽  
2012 ◽  
Vol 55 (4) ◽  
pp. 103-111 ◽  
Author(s):  
Hai Le Nguyen ◽  
Kiat Ruxrungtham ◽  
Constance Delaugerre
Keyword(s):  
Integrase Inhibitors ◽  
Genetic Barrier ◽  
Development Of Resistance ◽  
Hiv 1

3-Hydroxyphthaloyl β-Lactoglobulin. III. Antiviral Activity against Herpesviruses

1998 ◽  
Vol 9 (2) ◽  
pp. 177-184 ◽  
Author(s):  
AR Neurath ◽  
N Strick ◽  
Y-Y Li
Keyword(s):  
Antiviral Agents ◽  
Antiviral Agent ◽  
Major Protein ◽  
Compound I ◽  
Sexually Transmitted ◽  
Prophylactic Measures ◽  
Simplex Virus ◽  
Β Lactoglobulin ◽  
Hiv 1 ◽  
Hsv 1

The spread of sexually transmitted diseases, including human immunodeficiency virus type 1 (HIV-1) and herpesvirus infections, has continued unabated despite educational efforts spearheaded as a response to the HIV-1 epidemic. This suggests the need for prophylactic measures, including the application of topical antiviral agents. Chemical modification of bovine β-lactoglobulin (β-LG), the major protein of whey, by hydroxyphthalic anhydride (3HP) led to the generation of a potent HIV-1 inhibitor (designated 3HP-β-LG) shown to also have activity against herpes simplex virus types 1 and 2 (HSV-1, HSV-2). This report provides more detailed results concerning the anti-herpesvirus activity of 3HP-β-LG, indicating that this compound: (i) inhibited infection by human cytomegalovirus (HCMV), which is known to besexually transmitted; (ii) inactivated the infectivity of both HSV-1 and HSV-2; (iii) inhibited cell-to-cell transmission of HSV-1 and HSV-2; and (iv) bound to HSV-1, HSV-2 and HCMV virus particles and partially inhibited the binding of anti-glycoprotein E (gE) and anti-gC monoclonal antibodies to HSV-1 and HSV-2. The binding of 3HP-β-LG to the herpesviruses under study was inhibited by aggregated human IgG, suggesting that the respective viral Fc receptor is one of the target sites for 3HP-β-LG. In agreement with results on inhibition of HIV-1 infection, 3HP-β-LG appears to be the acid anhydride-modified protein of choice as an antiviral agent against herpesviruses.

scholarly journals Mechanism-Based Covalent Neuraminidase Inhibitors with Broad-Spectrum Influenza Antiviral Activity

Science ◽  
2013 ◽  
Vol 340 (6128) ◽  
pp. 71-75 ◽  
Author(s):  
Jin-Hyo Kim ◽  
Ricardo Resende ◽  
Tom Wennekes ◽  
Hong-Ming Chen ◽  
Nicole Bance ◽  
...  
Keyword(s):  
Broad Spectrum ◽  
Antiviral Agents ◽  
Neuraminidase Inhibitor ◽  
New Class ◽  
Development Of Resistance ◽  
Spectrum Activity ◽  
Future Utility ◽  
Drug Resistant Strains ◽  
Covalent Intermediate

Influenza antiviral agents play important roles in modulating disease severity and in controlling pandemics while vaccines are prepared, but the development of resistance to agents like the commonly used neuraminidase inhibitor oseltamivir may limit their future utility. We report here on a new class of specific, mechanism-based anti-influenza drugs that function through the formation of a stabilized covalent intermediate in the influenza neuraminidase enzyme, and we confirm this mode of action with structural and mechanistic studies. These compounds function in cell-based assays and in animal models, with efficacies comparable to that of the neuraminidase inhibitor zanamivir and with broad-spectrum activity against drug-resistant strains in vitro. The similarity of their structure to that of the natural substrate and their mechanism-based design make these attractive antiviral candidates.

scholarly journals Curcumin as an Antiviral Agent

Viruses ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 1242
Author(s):  
Morgan R. Jennings ◽  
Robin J. Parks
Keyword(s):  
Antimicrobial Agent ◽  
Broad Spectrum ◽  
Antiviral Agents ◽  
Antiviral Agent

Curcumin, the primary curcuminoid compound found in turmeric spice, has shown broad activity as an antimicrobial agent, limiting the replication of many different fungi, bacteria and viruses. In this review, we summarize recent studies supporting the development of curcumin and its derivatives as broad-spectrum antiviral agents.

scholarly journals Probing the Mechanistic Consequences of 5-Fluorine Substitution on Cytidine Nucleotide Analogue Incorporation by HIV-1 Reverse Transcriptase

2003 ◽  
Vol 14 (3) ◽  
pp. 115-125 ◽  
Author(s):  
Adrian S Ray ◽  
Raymond F Schinazi ◽  
Eisuke Murakami ◽  
Aravind Basavapathruni ◽  
Junxing Shi ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Antiviral Agents ◽  
Pyrimidine Ring ◽  
Resistance Mechanisms ◽  
Fluorine Substitution ◽  
Dna And Rna ◽  
Nucleotide Incorporation ◽  
Cellular Replication ◽  
Effective Use ◽  
Hiv 1

β-D and β-L-enantiomers of 2′,3′-dideoxycytidine analogues are potent chain-terminators and antimetabolites for viral and cellular replication. Seemingly small modifications markedly alter their antiviral and toxicity patterns. This review discusses previously published and recently obtained data on the effects of 5- and 2′-fluorine substitution on the pre-steady state incorporation of 2′-deoxycytidine-5′-monophosphate analogues by HIV-1 reverse transcriptase (RT) in light of their biological activity. The addition of fluorine at the 5-position of the pyrimidine ring altered the kinetic parameters for all nucleotides tested. Only the 5-fluorine substitution of the clinically relevant nucleosides (-)-β-L-2′,3′-dideoxy-3′-thia-5-fluoro-cytidine (L-FTC, Emtriva™), and (+)-β-D-2′,3′-dide-hydro-2′,3′-dideoxy-5-fluorocytidine (D-D4FC, Reverset™), caused a higher overall efficiency of nucleotide incorporation during both DNA- and RNA-directed synthesis. Enhanced incorporation by RT may in part explain the potency of these nucleosides against HIV-1. In other cases, a lack of correlation between RT incorporation in enzymatic assays and antiviral activity in cell culture illustrates the importance of other cellular factors in defining antiviral potency. The substitution of fluorine at the 2′ position of the deoxyribose ring negatively affects incorporation by RT indicating the steric gate of RT can detect electrostatic perturbations. Intriguing results pertaining to drug resistance have led to a better understanding of HIV-1 RT resistance mechanisms. These insights serve as a basis for understanding the mechanism of action for nucleoside analogues and, coupled with studies on other key enzymes, may lead to the more effective use of fluorine to enhance the potency and selectivity of antiviral agents.

scholarly journals In Vitro Selection of Highly Darunavir-Resistant and Replication-Competent HIV-1 Variants by Using a Mixture of Clinical HIV-1 Isolates Resistant to Multiple Conventional Protease Inhibitors

2010 ◽  
Vol 84 (22) ◽  
pp. 11961-11969 ◽  
Author(s):  
Yasuhiro Koh ◽  
Masayuki Amano ◽  
Tomomi Towata ◽  
Matthew Danish ◽  
Sofiya Leshchenko-Yashchuk ◽  
...  
Keyword(s):  
Homologous Recombination ◽  
In Vitro Selection ◽  
Multiple Drug ◽  
Drug Resistant ◽  
Genetic Barrier ◽  
Development Of Resistance ◽  
Multiple Drug Resistant ◽  
Moderately Resistant ◽  
Hiv 1

ABSTRACT We attempted to select HIV-1 variants resistant to darunavir (DRV), which potently inhibits the enzymatic activity and dimerization of protease and has a high genetic barrier to HIV-1 development of resistance to DRV. We conducted selection using a mixture of 8 highly multi-protease inhibitor (PI)-resistant, DRV-susceptible clinical HIV-1 variants (HIV-1MIX) containing 9 to 14 PI resistance-associated amino acid substitutions in protease. HIV-1MIX became highly resistant to DRV, with a 50% effective concentration (EC50) ∼333-fold greater than that against HIV-1NL4-3. HIV-1MIX at passage 51 (HIV-1MIXP51 ) replicated well in the presence of 5 μM DRV and contained 14 mutations. HIV-1MIXP51 was highly resistant to amprenavir, indinavir, nelfinavir, ritonavir, lopinavir, and atazanavir and moderately resistant to saquinavir and tipranavir. HIV-1MIXP51 had a resemblance with HIV-1C of the HIV-1MIX population, and selection using HIV-1C was also performed; however, its DRV resistance acquisition was substantially delayed. The H219Q and I223V substitutions in Gag, lacking in HIV-1CP51 , likely contributed to conferring a replication advantage on HIV-1MIXP51 by reducing intravirion cyclophilin A content. HIV-1MIXP51 apparently acquired the substitutions from another HIV-1 strain(s) of HIV-1MIX through possible homologous recombination. The present data suggest that the use of multiple drug-resistant HIV-1 isolates is of utility in selecting drug-resistant variants and that DRV would not easily permit HIV-1 to develop significant resistance; however, HIV-1 can develop high levels of DRV resistance when a variety of PI-resistant HIV-1 strains are generated, as seen in patients experiencing sequential PI failure, and ensuing homologous recombination takes place. HIV-1MIXP51 should be useful in elucidating the mechanisms of HIV-1 resistance to DRV and related agents.

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