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Special Issue "Recent Advances in the Development of Antiviral Agents"

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (31 January 2019)

Special Issue Editor

Guest Editor
Prof. Dr. Stefano Aquaro

Department of Pharmacy, Health and Nutritional Sciences Università della Calabria, Rende (CS), Italy
Website | E-Mail
Interests: virus evolution; macrophages; HIV pathogenesis; antivirals; HIV chemotherapy; neuroAIDS; mechanisms of virus entry; chemokines and chemokine receptors; role of astrocytes and neurones in HIV infection

Special Issue Information

Dear Colleagues, 

Viral infections inflict many serious human diseases, especially in the most developing countries, with very high mortality rates. New drug-resistant strains are continually emerging due to the high viral mutation rate, which makes it necessary to develop novel and possibly more potent antiviral compounds. All researchers working in this field are cordially invited to contribute original research papers or reviews to this Special Issue of Molecules, which will report on the design, synthesis, and evaluation of novel antiviral drug or microbicide candidates against viral infections, the identification of novel biological targets or therapeutic approaches and rationale, or studies about antiviral resistance mechanisms and strategies to prevent and/or circumvent them.

Prof. Dr. Stefano Aquaro
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Antivirials
  • Drug design
  • Drug synthesis
  • Antiviral activity
  • Viruses
  • Antiviral resistence
  • Virus evolution
  • Antiviral therapy
  • Virus entry
  • Virus replication
  • Viral enzimes
  • Virus phatogenesis

Published Papers (13 papers)

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Research

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Open AccessCommunication
In Vitro and in Vivo Antiviral Activity of Mizoribine Against Foot-And-Mouth Disease Virus
Molecules 2019, 24(9), 1723; https://doi.org/10.3390/molecules24091723
Received: 13 March 2019 / Revised: 22 April 2019 / Accepted: 24 April 2019 / Published: 3 May 2019
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Abstract
Foot-and-mouth disease (FMD) is a highly contagious viral disease of cloven-hoofed animals, which has significant economic consequences in affected countries. As the currently available vaccines against FMD provide no protection until 4–7 days post-vaccination, the only alternative method to control the spread of [...] Read more.
Foot-and-mouth disease (FMD) is a highly contagious viral disease of cloven-hoofed animals, which has significant economic consequences in affected countries. As the currently available vaccines against FMD provide no protection until 4–7 days post-vaccination, the only alternative method to control the spread of FMD virus (FMDV) during outbreaks is the application of antiviral agents. Hence, it is important to identify effective antiviral agents against FMDV infection. In this study, we found that mizoribine has potent antiviral activity against FMDV replication in IBRS-2 cells. A time-of-drug-addition assay demonstrated that mizoribine functions at the early stage of replication. Moreover, mizoribine also showed antiviral effect on FMDV in vivo. In summary, these results revealed that mizoribine could be a potential antiviral drug against FMDV. Full article
(This article belongs to the Special Issue Recent Advances in the Development of Antiviral Agents)
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Open AccessArticle
Field-Based Affinity Optimization of a Novel Azabicyclohexane Scaffold HIV-1 Entry Inhibitor
Molecules 2019, 24(8), 1581; https://doi.org/10.3390/molecules24081581
Received: 19 February 2019 / Revised: 19 April 2019 / Accepted: 20 April 2019 / Published: 22 April 2019
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Abstract
Small-molecule HIV-1 entry inhibitors are an extremely attractive therapeutic modality. We have previously demonstrated that the entry inhibitor class can be optimized by using computational means to identify and extend the chemotypes available. Here we demonstrate unique and differential effects of previously published [...] Read more.
Small-molecule HIV-1 entry inhibitors are an extremely attractive therapeutic modality. We have previously demonstrated that the entry inhibitor class can be optimized by using computational means to identify and extend the chemotypes available. Here we demonstrate unique and differential effects of previously published antiviral compounds on the gross structure of the HIV-1 Env complex, with an azabicyclohexane scaffolded inhibitor having a positive effect on glycoprotein thermostability. We demonstrate that modification of the methyltriazole-azaindole headgroup of these entry inhibitors directly effects the potency of the compounds, and substitution of the methyltriazole with an amine-oxadiazole increases the affinity of the compound 1000-fold over parental by improving the on-rate kinetic parameter. These findings support the continuing exploration of compounds that shift the conformational equilibrium of HIV-1 Env as a novel strategy to improve future inhibitor and vaccine design efforts. Full article
(This article belongs to the Special Issue Recent Advances in the Development of Antiviral Agents)
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Open AccessArticle
Chenodeoxycholic Acid from Bile Inhibits Influenza A Virus Replication via Blocking Nuclear Export of Viral Ribonucleoprotein Complexes
Molecules 2018, 23(12), 3315; https://doi.org/10.3390/molecules23123315
Received: 19 October 2018 / Revised: 10 December 2018 / Accepted: 12 December 2018 / Published: 14 December 2018
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Abstract
Influenza A virus (IAV) infection is still a major global threat for humans, especially for the risk groups: young children and the elderly. The currently licensed antiviral drugs target viral factors and are prone to viral resistance. In recent years, a few endogenous [...] Read more.
Influenza A virus (IAV) infection is still a major global threat for humans, especially for the risk groups: young children and the elderly. The currently licensed antiviral drugs target viral factors and are prone to viral resistance. In recent years, a few endogenous small molecules from host, such as estradiol and omega-3 polyunsaturated fatty acid (PUFA)-derived lipid mediator protection D1 (PD1), were demonstrated to be capable of inhibiting IAV infection. Chenodeoxycholic acid (CDCA), one of the main primary bile acids, is synthesized from cholesterol in the liver and classically functions in emulsification and absorption of dietary fats. Clinically, CDCA has been used in the treatment of patients with cholesterol gallstones for more than five decades. In this study, we showed that CDCA attenuated the replication of three subtypes of influenza A virus, including a highly pathogenic H5N1 strain, in A549 and MDCK cell cultures with IC50 ranging from 5.5 to 11.5 μM. Mechanistically, CDCA effectively restrained the nuclear export of viral ribonucleoprotein (vRNP) complexes. In conclusion, as an endogenous physiological small molecule, CDCA can inhibit IAV replication in vitro, at least in part, by blocking vRNP nuclear export, and affords further studies for development as a potential antiviral agent against IAV infections. Full article
(This article belongs to the Special Issue Recent Advances in the Development of Antiviral Agents)
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Open AccessArticle
Alteration of Intestinal Flora Stimulates Pulmonary microRNAs to Interfere with Host Antiviral Immunity in Influenza
Molecules 2018, 23(12), 3151; https://doi.org/10.3390/molecules23123151
Received: 30 October 2018 / Revised: 18 November 2018 / Accepted: 29 November 2018 / Published: 30 November 2018
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Abstract
The intestinal flora may be an important and modifiable factor that contributes to the immune response in influenza. To investigate the effect of intestinal flora alteration induced by antibiotic interference on microRNA (miRNA) communication in antiviral immunity, BALB/c mice received two weeks of [...] Read more.
The intestinal flora may be an important and modifiable factor that contributes to the immune response in influenza. To investigate the effect of intestinal flora alteration induced by antibiotic interference on microRNA (miRNA) communication in antiviral immunity, BALB/c mice received two weeks of antibiotic treatment before infection with the influenza A virus. The changes in intestinal flora and pulmonary flora were detected and analyzed by 16S ribosomal RNA (rRNA) gene sequencing. The amplification of the influenza virus in the lungs was measured by RT-PCR. The involvement of pulmonary miRNA was explored using miRNA microarray analysis. The results showed that the antibiotics destroyed the symbiotic relationship of the intestinal flora, resulting in a reduction in bacterial diversity, but they did not affect the pulmonary flora. The alteration of intestinal flora affected the expression of pulmonary miRNAs and resulted in an enhancement of pulmonary influenza virus amplification. The conclusion is that alteration of intestinal flora induced by antibiotic interference affected the expression of pulmonary miRNAs to interfere with host antiviral immunity, of which miR-146b and miR-29c might be good resources of resistance to influenza under antibiotic abuse. Full article
(This article belongs to the Special Issue Recent Advances in the Development of Antiviral Agents)
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Open AccessArticle
A Computational Approach for the Prediction of HIV Resistance Based on Amino Acid and Nucleotide Descriptors
Molecules 2018, 23(11), 2751; https://doi.org/10.3390/molecules23112751
Received: 12 September 2018 / Revised: 7 October 2018 / Accepted: 16 October 2018 / Published: 24 October 2018
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Abstract
The high variability of the human immunodeficiency virus (HIV) is an important cause of HIV resistance to reverse transcriptase and protease inhibitors. There are many variants of HIV type 1 (HIV-1) that can be used to model sequence-resistance relationships. Machine learning methods are [...] Read more.
The high variability of the human immunodeficiency virus (HIV) is an important cause of HIV resistance to reverse transcriptase and protease inhibitors. There are many variants of HIV type 1 (HIV-1) that can be used to model sequence-resistance relationships. Machine learning methods are widely and successfully used in new drug discovery. An emerging body of data regarding the interactions of small drug-like molecules with their protein targets provides the possibility of building models on “structure-property” relationships and analyzing the performance of various machine-learning techniques. In our research, we analyze several different types of descriptors in order to predict the resistance of HIV reverse transcriptase and protease to the marketed antiretroviral drugs using the Random Forest approach. First, we represented amino acid sequences as a set of short peptide fragments, which included several amino acid residues. Second, we represented nucleotide sequences as a set of fragments, which included several nucleotides. We compared these two approaches using open data from the Stanford HIV Drug Resistance Database. We have determined the factors that modulate the performance of prediction: in particular, we observed that the prediction performance was more sensitive to certain drugs than a type of the descriptor used. Full article
(This article belongs to the Special Issue Recent Advances in the Development of Antiviral Agents)
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Open AccessArticle
Synthesis and Evolution of Berberine Derivatives as a New Class of Antiviral Agents against Enterovirus 71 through the MEK/ERK Pathway and Autophagy
Molecules 2018, 23(8), 2084; https://doi.org/10.3390/molecules23082084
Received: 17 July 2018 / Revised: 14 August 2018 / Accepted: 16 August 2018 / Published: 20 August 2018
Cited by 2 | PDF Full-text (8860 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Taking berberine (BBR) as the lead, 23 new BBR derivatives were synthesized and examined for their antiviral activities against four different genotype enterovirus 71 (EV71) strains with a cytopathic effect (CPE) assay. Structure-activity relationship (SAR) studies indicated that introduction of a suitable substituent [...] Read more.
Taking berberine (BBR) as the lead, 23 new BBR derivatives were synthesized and examined for their antiviral activities against four different genotype enterovirus 71 (EV71) strains with a cytopathic effect (CPE) assay. Structure-activity relationship (SAR) studies indicated that introduction of a suitable substituent at the 9-position might be beneficial for potency. Among them, compound 2d exhibited most potent activities with IC50 values of 7.12–14.8 μM, similar to that of BBR. The effect of 2d was further confirmed in a dose-dependent manner both in RNA and protein level. The mechanism revealed that 2d could inhibit the activation of MEK/ERK signaling pathway. Meanwhile, it could suppress the EV71-induced autophagy by activating AKT and inhibiting the phosphorylation of JNK and PI3KIII proteins. We consider BBR derivatives to be a new family of anti-EV71 agents through targeting host components, with an advantage of broad-spectrum anti-EV71 potency. Full article
(This article belongs to the Special Issue Recent Advances in the Development of Antiviral Agents)
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Open AccessArticle
HIV-1 Integrase-Targeted Short Peptides Derived from a Viral Protein R Sequence
Molecules 2018, 23(8), 1858; https://doi.org/10.3390/molecules23081858
Received: 25 June 2018 / Revised: 18 July 2018 / Accepted: 23 July 2018 / Published: 26 July 2018
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Abstract
HIV-1 integrase (IN) inhibitors represent a new class of highly effective anti-AIDS therapeutics. Current FDA-approved IN strand transfer inhibitors (INSTIs) share a common mechanism of action that involves chelation of catalytic divalent metal ions. However, the emergence of IN mutants having reduced sensitivity [...] Read more.
HIV-1 integrase (IN) inhibitors represent a new class of highly effective anti-AIDS therapeutics. Current FDA-approved IN strand transfer inhibitors (INSTIs) share a common mechanism of action that involves chelation of catalytic divalent metal ions. However, the emergence of IN mutants having reduced sensitivity to these inhibitors underlies efforts to derive agents that antagonize IN function by alternate mechanisms. Integrase along with the 96-residue multifunctional accessory protein, viral protein R (Vpr), are both components of the HIV-1 pre-integration complex (PIC). Coordinated interactions within the PIC are important for viral replication. Herein, we report a 7-mer peptide based on the shortened Vpr (69–75) sequence containing a biotin group and a photo-reactive benzoylphenylalanyl residue, and which exhibits low micromolar IN inhibitory potency. Photo-crosslinking experiments have indicated that the peptide directly binds IN. The peptide does not interfere with IN-DNA interactions or induce higher-order, aberrant IN multimerization, suggesting a mode of action for the peptide that is distinct from clinically used INSTIs and developmental allosteric IN inhibitors. This compact Vpr-derived peptide may serve as a valuable pharmacological tool to identify a potential new pharmacologic site. Full article
(This article belongs to the Special Issue Recent Advances in the Development of Antiviral Agents)
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Review

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Open AccessReview
Carbazole Derivatives as Antiviral Agents: An Overview
Molecules 2019, 24(10), 1912; https://doi.org/10.3390/molecules24101912
Received: 10 April 2019 / Revised: 6 May 2019 / Accepted: 15 May 2019 / Published: 17 May 2019
PDF Full-text (623 KB)
Abstract
Keywords: carbazole; tetrahydrocarbazole; antiviral agents Full article
(This article belongs to the Special Issue Recent Advances in the Development of Antiviral Agents)
Open AccessReview
Hotoda’s Sequence and Anti-HIV Activity: Where Are We Now?
Molecules 2019, 24(7), 1417; https://doi.org/10.3390/molecules24071417
Received: 7 March 2019 / Revised: 2 April 2019 / Accepted: 5 April 2019 / Published: 10 April 2019
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Abstract
The pharmacological relevance of ODNs forming G-quadruplexes as anti-HIV agents has been extensively reported in the literature over the last few years. Recent detailed studies have elucidated the peculiar arrangement adopted by many G-quadruplex-based aptamers and provided insight into their mechanism of action. [...] Read more.
The pharmacological relevance of ODNs forming G-quadruplexes as anti-HIV agents has been extensively reported in the literature over the last few years. Recent detailed studies have elucidated the peculiar arrangement adopted by many G-quadruplex-based aptamers and provided insight into their mechanism of action. In this review, we have reported the history of a strong anti-HIV agent: the 6-mer d(TGGGAG) sequence, commonly called “Hotoda’s sequence”. In particular, all findings reported on this sequence and its modified sequences have been discussed considering the following research phases: (i) discovery of the first 5′-modified active d(TGGGAG) sequences; (ii) synthesis of a variety of end-modified d(TGGGAG) sequences; (iii) biophysical and NMR investigations of natural and modified Hotoda’s sequences; (iv); kinetic studies on the most active 5′-modified d(TGGGAG) sequences; and (v) extensive anti-HIV screening of G-quadruplexes formed by d(TGGGAG) sequences. This review aims to clarify all results obtained over the years on Hotoda’s sequence, revealing its potentiality as a strong anti-HIV agent (EC50 = 14 nM). Full article
(This article belongs to the Special Issue Recent Advances in the Development of Antiviral Agents)
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Open AccessReview
CRISPR/Cas9-Based Antiviral Strategy: Current Status and the Potential Challenge
Molecules 2019, 24(7), 1349; https://doi.org/10.3390/molecules24071349
Received: 15 March 2019 / Revised: 29 March 2019 / Accepted: 4 April 2019 / Published: 5 April 2019
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Abstract
From its unexpected discovery as a bacterial adaptive immune system to its countless applications as one of the most versatile gene-editing tools, the CRISPR/Cas9 system has revolutionized every field of life science. Virology is no exception to this ever-growing list of CRISPR/Cas9-based applications. [...] Read more.
From its unexpected discovery as a bacterial adaptive immune system to its countless applications as one of the most versatile gene-editing tools, the CRISPR/Cas9 system has revolutionized every field of life science. Virology is no exception to this ever-growing list of CRISPR/Cas9-based applications. Direct manipulation of a virus genome by CRISPR/Cas9 has enabled a systematic study of cis-elements and trans-elements encoded in a virus genome. In addition, this virus genome-specific mutagenesis by CRISPR/Cas9 was further funneled into the development of a novel class of antiviral therapy targeting many incurable chronic viral infections. In this review, a general concept on the CRISPR/Cas9-based antiviral strategy will be described first. To understand the current status of the CRISPR/Cas9-based antiviral approach, a series of recently published antiviral studies involving CRISPR/Cas9-mediated control of several clinically-relevant viruses including human immunodeficiency virus, hepatitis B virus, herpesviruses, human papillomavirus, and other viruses will be presented. Lastly, the potential challenge and future prospect for successful clinical translation of this CRISPR/Cas9-based antiviral method will be discussed. Full article
(This article belongs to the Special Issue Recent Advances in the Development of Antiviral Agents)
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Open AccessReview
Novel Therapeutics for Epstein–Barr Virus
Molecules 2019, 24(5), 997; https://doi.org/10.3390/molecules24050997
Received: 15 February 2019 / Revised: 1 March 2019 / Accepted: 4 March 2019 / Published: 12 March 2019
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Abstract
Epstein–Barr virus (EBV) is a human γ-herpesvirus that infects up to 95% of the adult population. Primary EBV infection usually occurs during childhood and is generally asymptomatic, though the virus can cause infectious mononucleosis in 35–50% of the cases when infection occurs later [...] Read more.
Epstein–Barr virus (EBV) is a human γ-herpesvirus that infects up to 95% of the adult population. Primary EBV infection usually occurs during childhood and is generally asymptomatic, though the virus can cause infectious mononucleosis in 35–50% of the cases when infection occurs later in life. EBV infects mainly B-cells and epithelial cells, establishing latency in resting memory B-cells and possibly also in epithelial cells. EBV is recognized as an oncogenic virus but in immunocompetent hosts, EBV reactivation is controlled by the immune response preventing transformation in vivo. Under immunosuppression, regardless of the cause, the immune system can lose control of EBV replication, which may result in the appearance of neoplasms. The primary malignancies related to EBV are B-cell lymphomas and nasopharyngeal carcinoma, which reflects the primary cell targets of viral infection in vivo. Although a number of antivirals were proven to inhibit EBV replication in vitro, they had limited success in the clinic and to date no antiviral drug has been approved for the treatment of EBV infections. We review here the antiviral drugs that have been evaluated in the clinic to treat EBV infections and discuss novel molecules with anti-EBV activity under investigation as well as new strategies to treat EBV-related diseases. Full article
(This article belongs to the Special Issue Recent Advances in the Development of Antiviral Agents)
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Open AccessReview
CCR5/CXCR4 Dual Antagonism for the Improvement of HIV Infection Therapy
Molecules 2019, 24(3), 550; https://doi.org/10.3390/molecules24030550
Received: 15 January 2019 / Revised: 30 January 2019 / Accepted: 1 February 2019 / Published: 2 February 2019
PDF Full-text (3859 KB) | HTML Full-text | XML Full-text
Abstract
HIV entry in the host cell requires the interaction with the CD4 membrane receptor, and depends on the activation of one or both co-receptors CCR5 and CXCR4. Former selective co-receptor antagonists, acting at early stages of infection, are able to impair the receptor [...] Read more.
HIV entry in the host cell requires the interaction with the CD4 membrane receptor, and depends on the activation of one or both co-receptors CCR5 and CXCR4. Former selective co-receptor antagonists, acting at early stages of infection, are able to impair the receptor functions, preventing the viral spread toward AIDS. Due to the capability of HIV to develop resistance by switching from CCR5 to CXCR4, dual co-receptor antagonists could represent the next generation of AIDS prophylaxis drugs. We herein present a survey on relevant results published in the last few years on compounds acting simultaneously on both co-receptors, potentially useful as preventing agents or in combination with classical anti-retroviral drugs based therapy. Full article
(This article belongs to the Special Issue Recent Advances in the Development of Antiviral Agents)
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Other

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Open AccessBrief Report
Combining New Non-Nucleoside Reverse Transcriptase Inhibitors (RTIs) with AZT Results in Strong Synergism against Multi-RTI-Resistant HIV-1 Strains
Molecules 2018, 23(7), 1599; https://doi.org/10.3390/molecules23071599
Received: 24 May 2018 / Revised: 21 June 2018 / Accepted: 28 June 2018 / Published: 2 July 2018
PDF Full-text (616 KB) | HTML Full-text | XML Full-text
Abstract
Reverse transcriptase inhibitors (RTIs), including nucleoside RTIs (NRTIs) and non-nucleoside RTIs (NNRTIs), are critical antiretroviral drugs for the treatment of human immunodeficiency virus (HIV) infection. Emergence of multi-RTI resistance calls for the development of more potent therapeutics or regimens against RTI-resistant strains. Here, [...] Read more.
Reverse transcriptase inhibitors (RTIs), including nucleoside RTIs (NRTIs) and non-nucleoside RTIs (NNRTIs), are critical antiretroviral drugs for the treatment of human immunodeficiency virus (HIV) infection. Emergence of multi-RTI resistance calls for the development of more potent therapeutics or regimens against RTI-resistant strains. Here, we demonstrated that combining azidothymidine (AZT) with a new NNRTIs under development, diarylpyridine (DAPA)-2e, diarylanilin (DAAN)-14h, or DAAN-15h, resulted in strong synergism against infection by divergent HIV-1 strains, including those resistant to NRTIs and NNRTIs, suggesting the potential for developing these novel NNRTIs as salvage therapy for HIV/acquired immune deficiency syndrome (AIDS) patients. Full article
(This article belongs to the Special Issue Recent Advances in the Development of Antiviral Agents)
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