Binding of Multivalent Anionic Porphyrins to V3 Loop Fragments of an HIV-1 Envelope and Their Antiviral Activity

Several compounds, including the triphenylmethane derivative aurintricarboxylic acid (ATA) and porphyrins, were reported to inhibit the binding of anti-V3 loop-specific antibodies to the V3 loop of gp120 from HIV-1 III-B and to have antiviral activity, probably due to interference with the biological function of the V3 loop. However, these compounds can be applied to antiviral chemotherapy only if they interact with envelope glycoproteins from a multitude of epidemic HIV-1 strains and inhibit their replication. Since recombinant envelope glycoproteins, synthetic peptides and anti-V3 monoclonal antibodies may not be available for these HIV-1 strains, alternative assays are needed to prescreen different compounds for potential antiviral activity against these viruses. Results presented here indicate that: (1) virions of HIV-1 MN, most closely related to primary HIV-1 isolates from European and North American countries, and human anti-HIV-1 antibodies, can also be used for rapid prescreening of antiviral agents, (2) compounds with antiviral activity against HIV-1 MN, discerned by site-directed immunoassays, inhibited the reaction of human anti-HIV-1 with a V3 loop consensus peptide corresponding to European/North American HIV-1 isolates, and (3) meso-tetra (4-carboxyphenyl) porphine (MTCPP), one of the most potent inhibitors of HIV-1 replication selected on the basis of site-directed immunoassays, preferentially attached to the V3 loop of gp120.

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Rapid Prescreening for Antiviral Agents against HIV-1 Based on Their Inhibitory Activity in Site-Directed Immunoassays. II. Porphyrins Reacting with the V3 Loop of gp120

Antiviral Chemistry and Chemotherapy ◽

10.1177/095632029200300108 ◽

1992 ◽

Vol 3 (1) ◽

pp. 55-63 ◽

Cited By ~ 23

Author(s):

A. R. Neurath ◽

N. Strick ◽

P. Haberfield ◽

S. Jiang

Keyword(s):

Antiviral Activity ◽

Inhibitory Activity ◽

Antiviral Agents ◽

V3 Loop ◽

Antiviral Compounds ◽

Porphyrin Derivatives ◽

Immunodeficiency Virus ◽

Glycoprotein Gp120 ◽

The Relationship ◽

Hiv 1

Recent observations that haernin inhibited the replication of the human immunodeficiency virus (HIV-1) and the reaction between the HIV-1 envelope glycoprotein gp120 and antibodies specific for the V3 hypervariable loop of this glycoprotein were an enticement to determine whether or not additional porphyrins had similar activities. Several porphyrin derivatives, particularly meso-tetra (4-carboxyphenyl) porphine, were more potent inhibitors of HIV-1 replication than haernin. They blocked the binding of homologous antibodies to synthetic peptides corresponding to V3 hypervariable loops of 21 distinct HIV-1 isolates, and inhibited the replication in lymphocytic (MT-2) and promonocyte (U937) cell lines of several HIV-1 isolates, tested (IIIB, RF, SF-2, and MN). Compounds with inhibitory activity had a tetrapyrrole ring and, carboxyl or sulphonate groups. However, antiviral activity depended on minor structural difference's between distinct derivatives endowed with these two features. Metalloporphyrins had a drastically reduced antiviral activity in comparison with the corresponding porphyrins. An understanding of the relationship between the structure of porphyrins and their antiviral effects, perceptible from the results presented, is expected to lead to the design of additional derivatives with more potent antiviral activity and to unravelling of molecular details involved in the association between the V3 loop of gp120 and antiviral compounds targeted to this loop.

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Elucidating the Disparate Inhibitory Mechanisms of Novel 1-Heteroaryl1,3-Propanediamine Derivatives and Maraviroc towards C-C Chemokine Receptor 5: Insights for Structural Modifications in HIV-1 Drug Discovery

Medicinal Chemistry ◽

10.2174/1573406417666201208122110 ◽

2020 ◽

Vol 17 ◽

Author(s):

Patrick Appiah-Kubi ◽

Fisayo Andrew Olotu ◽

Mahmoud E. S. Soliman

Keyword(s):

Drug Discovery ◽

Chemokine Receptor ◽

Competitive Inhibition ◽

Dynamic Effect ◽

Triazole Ring ◽

Internal Dynamic ◽

V3 Loop ◽

Structural Modifications ◽

Hiv 1 ◽

Chemokine Receptor 5

Introduction: Blocking Human Immunodeficiency Virus type 1 (HIV-1) entry via C-C chemokine receptor 5 (CCR5) inhibition has remained an essential strategy in HIV drug discovery. This underlies the development of CCR5 blockers, such as Maraviroc, which, however, elicits undesirable side effects despite its potency. Background: Recent lead optimization efforts led to the discovery of novel 1-heteroaryl-1,3-propanediamine derivatives; Compd-21 and -34, which were ~3 times more potent than Maraviroc, with improved pharmacokinetics. However, atomistic molecular interaction mechanism of how slight structural variance between these inhibitors significantly affects their binding profiles have not been elucidated. Method: This study employed explicit lipid bilayer molecular dynamics (MD) simulations, and advance analyses to explore these inhibitory discrepancies. Results: Findings revealed that the thiophene moiety substitution common to Compd-21 and -34 enhanced their CCR5- inhibitory activities due to complementary high-affinity interactions with Trp862.60, Tyr1083.32, Tyr2516.51, Glu2837.39. These cumulatively accounted for their ΔGbind which were higher than Maraviroc. Binding dynamics further revealed that the compounds mediated direct competitive inhibition at CCR5 by blocking the gp120 V3 loop. Furthermore, constituent tropane and triazole moieties in the compounds commonly engaged in interactions with Glu2837.39 and Trp862.60, respectively. Structural analyses also revealed that both Compd-21 and -34 elicited distinct internal dynamic effect on CCR5 relative to Maraviroc. Conclusion: Structural modifications at the thiophene substituent and the addition of new functional groups to the triazole ring may enhance inhibitor competition with gp120 V3-loop. Findings herein highlighted would contribute to future structure-based design of inhibitors of HIV-1 CCR5 with improved potencies.

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SUMOylation of SAMHD1 at Lysine 595 is required for HIV-1 restriction in non-cycling cells

Nature Communications ◽

10.1038/s41467-021-24802-5 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Charlotte Martinat ◽

Arthur Cormier ◽

Joëlle Tobaly-Tapiero ◽

Noé Palmic ◽

Nicoletta Casartelli ◽

...

Keyword(s):

Antiviral Activity ◽

Reverse Transcription ◽

Immune Cells ◽

Viral Restriction ◽

Antiviral Function ◽

Hiv 1 ◽

Constitutively Active

AbstractSAMHD1 is a cellular triphosphohydrolase (dNTPase) proposed to inhibit HIV-1 reverse transcription in non-cycling immune cells by limiting the supply of the dNTP substrates. Yet, phosphorylation of T592 downregulates SAMHD1 antiviral activity, but not its dNTPase function, implying that additional mechanisms contribute to viral restriction. Here, we show that SAMHD1 is SUMOylated on residue K595, a modification that relies on the presence of a proximal SUMO-interacting motif (SIM). Loss of K595 SUMOylation suppresses the restriction activity of SAMHD1, even in the context of the constitutively active phospho-ablative T592A mutant but has no impact on dNTP depletion. Conversely, the artificial fusion of SUMO2 to a non-SUMOylatable inactive SAMHD1 variant restores its antiviral function, a phenotype that is reversed by the phosphomimetic T592E mutation. Collectively, our observations clearly establish that lack of T592 phosphorylation cannot fully account for the restriction activity of SAMHD1. We find that SUMOylation of K595 is required to stimulate a dNTPase-independent antiviral activity in non-cycling immune cells, an effect that is antagonized by cyclin/CDK-dependent phosphorylation of T592 in cycling cells.

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Design, Synthesis, and antiviral activity of a series of CD4-mimetic small-molecule HIV-1 entry inhibitors

Bioorganic & Medicinal Chemistry ◽

10.1016/j.bmc.2021.116000 ◽

2021 ◽

pp. 116000

Author(s):

Francesca Curreli ◽

Shahad Ahmed ◽

Sofia M. Benedict Victor ◽

Ildar R. Iusupov ◽

Evgeny A. Spiridonov ◽

...

Keyword(s):

Antiviral Activity ◽

Small Molecule ◽

Design Synthesis ◽

Entry Inhibitors ◽

Hiv 1

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Flavonol 7-O-Glucoside Herbacitrin Inhibits HIV-1 Replication through Simultaneous Integrase and Reverse Transcriptase Inhibition

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2019/1064793 ◽

2019 ◽

Vol 2019 ◽

pp. 1-6 ◽

Cited By ~ 3

Author(s):

Éva Áy ◽

Attila Hunyadi ◽

Mária Mezei ◽

János Minárovits ◽

Judit Hohmann

Keyword(s):

Antiviral Activity ◽

Reverse Transcriptase ◽

Cell Cultures ◽

Core Protein ◽

Integrase Inhibitor ◽

Host Cells ◽

Cytotoxic Activities ◽

Protein Levels ◽

Hiv 1 ◽

Antiretroviral Activity

Here we report the evaluation of the antiretroviral effect of two flavonoid 7-O-glucosides, herbacitrin (1) and gossypitrin (2), together with quercetin (3), a well-studied flavonol. Antiviral activity of the flavonoids was assessed by analyzing HIV-1 p24 core protein levels in the supernatants of HIV-1 infected MT-4 and MT-2 cell cultures. The compounds showed mild to weak cytotoxic activities on the host cells; herbacitrin was the strongest in this regard (CC50=27.8 and 63.64 μM on MT-4 and MT-2 cells, respectively). In nontoxic concentrations, herbacitrin and quercetin reduced HIV-1 replication, whereas gossypitrin was ineffective. Herbacitrin was found to inhibit reverse transcriptase at 21.5 μM, while it was a more potent integrase inhibitor already active at 2.15 μM. Therefore, our observations suggest that herbacitrin exerts antiretroviral activity through simultaneously acting on these two targets of HIV-1 and that integrase inhibition might play a major role in this activity.

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Identification of the Envelope V3 Loop as a Determinant of a CD4-Negative Neuronal Cell Tropism for HIV-1

Virology ◽

10.1006/viro.1996.0158 ◽

1996 ◽

Vol 217 (2) ◽

pp. 613-617 ◽

Cited By ~ 38

Author(s):

J.ROBERTO TRUJILLO ◽

WEI-KUNG WANG ◽

TUN-HOU LEE ◽

MAX ESSEX

Keyword(s):

Neuronal Cell ◽

V3 Loop ◽

Cell Tropism ◽

Hiv 1

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Antiviral activity of derivatized dextrans on HIV-1 infection of primary macrophages and blood lymphocytes

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease ◽

10.1016/s0925-4439(97)00057-4 ◽

1997 ◽

Vol 1362 (1) ◽

pp. 47-55 ◽

Cited By ~ 4

Author(s):

Nabila Seddiki ◽

Elisabeth Mbemba ◽

Didier Letourneur ◽

Loyda Ylisastigui ◽

Abdelaziz Benjouad ◽

...

Keyword(s):

Antiviral Activity ◽

Blood Lymphocytes ◽

Hiv 1

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Towards Inhibition of Vif-APOBEC3G Interaction: Which Protein to Target?

Advances in Virology ◽

10.1155/2010/649315 ◽

2010 ◽

Vol 2010 ◽

pp. 1-10 ◽

Cited By ~ 4

Author(s):

Iris Cadima-Couto ◽

Joao Goncalves

Keyword(s):

Antiviral Activity ◽

Protein Binding ◽

Mechanism Of Action ◽

Cellular Immunity ◽

Viral Infectivity ◽

Binding Partners ◽

Viral Infectivity Factor ◽

Vif Protein ◽

Hiv 1 ◽

Antiretroviral Activity

APOBEC proteins appeared in the cellular battle against HIV-1 as part of intrinsic cellular immunity. The antiretroviral activity of some of these proteins is overtaken by the action of HIV-1 Viral Infectivity Factor (Vif) protein. Since the discovery of APOBEC3G (A3G) as an antiviral factor, many advances have been made to understand its mechanism of action in the cell and how Vif acts in order to counteract its activity. The mainstream concept is that Vif overcomes the innate antiviral activity of A3G by direct protein binding and promoting its degradation via the cellular ubiquitin/proteasomal pathway. Vif may also inhibit A3G through mechanisms independent of proteasomal degradation. Binding of Vif to A3G is essential for its degradation since disruption of this interaction is predicted to stimulate intracellular antiviral immunity. In this paper we will discuss the different binding partners between both proteins as one of the major challenges for the development of new antiviral drugs.

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