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Viruses
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HIV-1 Entry Inhibitors
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HIV-1 Entry Inhibitors

A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Viral Immunology, Vaccines, and Antivirals".

Deadline for manuscript submissions: closed (31 May 2023) | Viewed by 10096

Special Issue Editor

Dr. Asim Debnath

E-Mail Website
Guest Editor
Laboratory of Molecular Modeling & Drug Design, Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY, USA
Interests: HIV; SARS-CoV-2; drug discovery
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

During the last two decades, our understanding of the human immunodeficiency virus-1 (HIV-1) attachment to the host cell membrane, followed by fusion and entry ( often collectively termed as “entry”), contributed significantly to developing small molecule and peptide-based inhibitors. The United States Food and Drug Administration (FDA) approved several drugs that target both host cell receptors, such as CD4 and CCR5, and virus envelope glycoproteins, such as gp41 and gp120, which are involved in the different stages of the entry pathway. Fusion inhibitor, Enfuvirtide (Fuzeone), a peptide-based drug that targets envelope glycoprotein gp41, was approved in 2003. CCR5 antagonist, Maraviroc (Selzentry), was approved in 2007. A post-attachment inhibitor, Ibalizumab-uiyk (Trogarzo), a non-immunosuppressive humanized monoclonal antibody that binds to host cell receptor CD4, was approved in 2018. In 2020, Fostemsavir (Rukobia), an attachment inhibitor that targets the envelope glycoprotein gp120, was approved. The researchers from multidisciplinary areas contributed to the immense progress made in this area. In this Special Issue, we will endeavor to portray those contributions and focus our effort on the entry mechanism and the progress made in discovering entry inhibitors that may change the landscape of treating HIV-1-infected patients.

Dr. Asim Debnath
Guest Editor

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Published Papers (5 papers)

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Research

13 pages, 1596 KiB  
Article
Temsavir Modulates HIV-1 Envelope Conformation by Decreasing Its Proteolytic Cleavage
by Marianne Boutin, Halima Medjahed, Manon Nayrac, Rishikesh Lotke, Gabrielle Gendron-Lepage, Catherine Bourassa, Daniel Sauter, Jonathan Richard and Andrés Finzi
Viruses 2023, 15(5), 1189; https://doi.org/10.3390/v15051189 - 18 May 2023
Cited by 1 | Viewed by 1771
Abstract
HIV-1 envelope glycoproteins (Envs) mediate viral entry and represent a target of choice for small molecule inhibitors. One of them, temsavir (BMS-626529) prevents the interaction of the host cell receptor CD4 with Env by binding the pocket under the β20–β21 loop of the [...] Read more.
HIV-1 envelope glycoproteins (Envs) mediate viral entry and represent a target of choice for small molecule inhibitors. One of them, temsavir (BMS-626529) prevents the interaction of the host cell receptor CD4 with Env by binding the pocket under the β20–β21 loop of the Env subunit gp120. Along with its capacity to prevent viral entry, temsavir stabilizes Env in its “closed” conformation. We recently reported that temsavir affects glycosylation, proteolytic processing, and overall conformation of Env. Here, we extend these results to a panel of primary Envs and infectious molecular clones (IMCs), where we observe a heterogeneous impact on Env cleavage and conformation. Our results suggest that the effect of temsavir on Env conformation is associated with its capacity to decrease Env processing. Indeed, we found that the effect of temsavir on Env processing affects the recognition of HIV-1-infected cells by broadly neutralizing antibodies and correlates with their capacity to mediate antibody-dependent cellular cytotoxicity (ADCC). Full article
(This article belongs to the Special Issue HIV-1 Entry Inhibitors)
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18 pages, 6099 KiB  
Article
Piperidine CD4-Mimetic Compounds Expose Vulnerable Env Epitopes Sensitizing HIV-1-Infected Cells to ADCC
by Shilei Ding, William D. Tolbert, Huile Zhu, Daniel Lee, Lorie Marchitto, Tyler Higgins, Xuchen Zhao, Dung Nguyen, Rebekah Sherburn, Jonathan Richard, Gabrielle Gendron-Lepage, Halima Medjahed, Mohammadjavad Mohammadi, Cameron Abrams, Marzena Pazgier, Amos B. Smith III and Andrés Finzi
Viruses 2023, 15(5), 1185; https://doi.org/10.3390/v15051185 - 17 May 2023
Cited by 7 | Viewed by 1951
Abstract
The ability of the HIV-1 accessory proteins Nef and Vpu to decrease CD4 levels contributes to the protection of infected cells from antibody-dependent cellular cytotoxicity (ADCC) by preventing the exposure of Env vulnerable epitopes. Small-molecule CD4 mimetics (CD4mc) based on the indane and [...] Read more.
The ability of the HIV-1 accessory proteins Nef and Vpu to decrease CD4 levels contributes to the protection of infected cells from antibody-dependent cellular cytotoxicity (ADCC) by preventing the exposure of Env vulnerable epitopes. Small-molecule CD4 mimetics (CD4mc) based on the indane and piperidine scaffolds such as (+)-BNM-III-170 and (S)-MCG-IV-210 sensitize HIV-1-infected cells to ADCC by exposing CD4-induced (CD4i) epitopes recognized by non-neutralizing antibodies that are abundantly present in plasma from people living with HIV. Here, we characterize a new family of CD4mc, (S)-MCG-IV-210 derivatives, based on the piperidine scaffold which engages the gp120 within the Phe43 cavity by targeting the highly conserved Asp368 Env residue. We utilized structure-based approaches and developed a series of piperidine analogs with improved activity to inhibit the infection of difficult-to-neutralize tier-2 viruses and sensitize infected cells to ADCC mediated by HIV+ plasma. Moreover, the new analogs formed an H-bond with the α-carboxylic acid group of Asp368, opening a new avenue to enlarge the breadth of this family of anti-Env small molecules. Overall, the new structural and biological attributes of these molecules make them good candidates for strategies aimed at the elimination of HIV-1-infected cells. Full article
(This article belongs to the Special Issue HIV-1 Entry Inhibitors)
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15 pages, 2475 KiB  
Article
An Artificial Peptide-Based Bifunctional HIV-1 Entry Inhibitor That Interferes with Viral Glycoprotein-41 Six-Helix Bundle Formation and Antagonizes CCR5 on the Host Cell Membrane
by Chao Wang, Qing Li, Lujia Sun, Xinling Wang, Huan Wang, Wenpeng Zhang, Jiahui Li, Yang Liu, Lu Lu and Shibo Jiang
Viruses 2023, 15(5), 1038; https://doi.org/10.3390/v15051038 - 23 Apr 2023
Cited by 1 | Viewed by 2273
Abstract
Human immunodeficiency virus type 1 (HIV-1) is characterized by high variability and drug resistance. This has necessitated the development of antivirals with a new chemotype and therapy. We previously identified an artificial peptide with non-native protein sequence, AP3, with the potential to inhibit [...] Read more.
Human immunodeficiency virus type 1 (HIV-1) is characterized by high variability and drug resistance. This has necessitated the development of antivirals with a new chemotype and therapy. We previously identified an artificial peptide with non-native protein sequence, AP3, with the potential to inhibit HIV-1 fusion through targeting hydrophobic grooves on the N-terminal heptad repeat trimer of viral glycoprotein gp41. Here, a small-molecule HIV-1 inhibitor targeting chemokine coreceptor CCR5 on the host cell was integrated into the AP3 peptide, producing a novel dual-target inhibitor with improved activity against multiple HIV-1 strains including those resistant to the currently used anti-HIV-1 drug enfuvirtide. Its superior antiviral potency in comparison with the respective pharmacophoric moieties is in consonance with the dual binding of viral gp41 and host factor CCR5. Therefore, our work provides a potent artificial peptide-based bifunctional HIV-1 entry inhibitor and highlights the multitarget-directed ligands approach in the development of novel therapeutic anti-HIV-1 agents. Full article
(This article belongs to the Special Issue HIV-1 Entry Inhibitors)
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12 pages, 2062 KiB  
Article
Targeting a Conserved Lysine in the Hydrophobic Pocket of HIV-1 gp41 Improves Small Molecule Antiviral Activity
by Li He, Guangyan Zhou, Vladimir Sofiyev, Eddie Garcia, Newton Nguyen, Kathy H. Li and Miriam Gochin
Viruses 2022, 14(12), 2703; https://doi.org/10.3390/v14122703 - 2 Dec 2022
Cited by 1 | Viewed by 1609
Abstract
Human Immunodeficiency virus (HIV-1) fusion is mediated by glycoprotein-41, a protein that has not been widely exploited as a drug target. Small molecules directed at the gp41 ectodomain have proved to be poorly drug-like, having moderate efficacy, high hydrophobicity and/or high molecular weight. [...] Read more.
Human Immunodeficiency virus (HIV-1) fusion is mediated by glycoprotein-41, a protein that has not been widely exploited as a drug target. Small molecules directed at the gp41 ectodomain have proved to be poorly drug-like, having moderate efficacy, high hydrophobicity and/or high molecular weight. We recently investigated conversion of a fairly potent hydrophobic inhibitor into a covalent binder, by modifying it to react with a lysine residue on the protein. We demonstrated a 10-fold improvement in antiviral efficacy. Here, we continue this study, utilizing instead molecules with better inherent drug-like properties. Molecules possessing low to no antiviral activity as equilibrium binders were converted into µM inhibitors upon addition of an electrophilic warhead in the form of a sulfotetrafluorophenyl (STP) activated ester. We confirmed specificity for gp41 and for entry. The small size of the inhibitors described here offers an opportunity to expand their reach into neighboring pockets while retaining drug-likeness. STP esterification of equilibrium binders is a promising avenue to explore for inhibiting HIV-1 entry. Many gp41 targeting molecules studied over the years possess carboxylic acid groups which can be easily converted into the corresponding STP ester. It may be worth the effort to evaluate a library of such inhibitors as a way forward to small molecule inhibition of fusion of HIV and possibly other enveloped viruses. Full article
(This article belongs to the Special Issue HIV-1 Entry Inhibitors)
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13 pages, 2345 KiB  
Article
Comparative Pharmacokinetics of a Dual Inhibitor of HIV-1, NBD-14189, in Rats and Dogs with a Proof-of-Concept Evaluation of Antiviral Potency in SCID-hu Mouse Model
by Cheryl A. Stoddart, Francesca Curreli, Stephen Horrigan, Andrea Altieri, Alexander V. Kurkin and Asim K. Debnath
Viruses 2022, 14(10), 2268; https://doi.org/10.3390/v14102268 - 16 Oct 2022
Cited by 1 | Viewed by 1778
Abstract
We earlier reported substantial progress in designing gp120 antagonists. Notably, we discovered that NBD-14189 is not only the most active gp120 antagonist but also shows antiviral activity against HIV-1 Reverse Transcriptase (RT). We also confirmed its binding to HIV-1 RT by X-ray crystallography. [...] Read more.
We earlier reported substantial progress in designing gp120 antagonists. Notably, we discovered that NBD-14189 is not only the most active gp120 antagonist but also shows antiviral activity against HIV-1 Reverse Transcriptase (RT). We also confirmed its binding to HIV-1 RT by X-ray crystallography. The dual inhibition is highly significant because, intriguingly, this compound bridges the dNTP and NNRTI-binding sites and inhibits the polymerase activity of isolated RT in the enzymatic assay. This novel finding is expected to lead to new avenues in designing a novel class of HIV-1 dual inhibitors. Therefore, we needed to advance this inhibitor to preclinical assessment. To this end, we report the pharmacokinetics (PK) study of NBD-14189 in rats and dogs. Subsequently, we assessed the toxicity and therapeutic efficacy in vivo in the SCID-hu Thy/Liv mouse model. The PK data indicated a favorable half-life (t1/2) and excellent oral bioavailability (%F = 61%). NBD-14189 did not show any measurable toxicity in the mice, and treatment reduced HIV replication at 300 mg/kg per day in the absence of clear evidence of protection from HIV-mediated human thymocyte depletion. The data indicated the potential of this inhibitor as an anti-HIV-1 agent and needs to be assessed in a non-human primate (NHP) model. Full article
(This article belongs to the Special Issue HIV-1 Entry Inhibitors)
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