Recent Advances in HIV-1 Gag Inhibitor Design and Development

Dick, Alexej; Simon, Chantal

doi:10.3390/molecules25071687

Cited by 22 publications

(24 citation statements)

References 149 publications

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“…An in-vitro CA-SP1 cleavage assay can be utilized to screen the resistant mutants, which can be helpful in rational designing of novel drugs [ 43 ]. Furthermore, capsid protein can be targeted with highly potent and potentially long-acting capsid inhibitors along with MIs [ 55 ].…”

Section: Discussionmentioning

confidence: 99%

A single G10T polymorphism in HIV-1 subtype C Gag-SP1 regulates sensitivity to maturation inhibitors

Ghimire

Timilsina

et al. 2021

Retrovirology

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Background Maturation inhibitors (MIs) potently block HIV-1 maturation by inhibiting the cleavage of the capsid protein and spacer peptide 1 (CA-SP1). Bevirimat (BVM), a highly efficacious first-in-class MI against HIV-1 subtype B isolates, elicited sub-optimal efficacy in clinical trials due to polymorphisms in the CA-SP1 region of the Gag protein (SP1:V7A). HIV-1 subtype C inherently contains this polymorphism thus conferring BVM resistance, however it displayed sensitivity to second generation BVM analogs. Results In this study, we have assessed the efficacy of three novel second-generation MIs (BVM analogs: CV-8611, CV-8612, CV-8613) against HIV-1 subtype B and C isolates. The BVM analogs were potent inhibitors of both HIV-1 subtype B (NL4-3) and subtype C (K3016) viruses. Serial passaging of the subtype C, K3016 virus strain in the presence of BVM analogs led to identification of two mutant viruses—Gag SP1:A1V and CA:I201V. While the SP1:A1V mutant was resistant to the MIs, the CA:I120V mutant displayed partial resistance and a MI-dependent phenotype. Further analysis of the activity of the BVM analogs against two additional HIV-1 subtype C strains, IndieC1 and ZM247 revealed that they had reduced sensitivity as compared to K3016. Sequence analysis of the three viruses identified two polymorphisms at SP1 residues 9 and 10 (K3016: N9, G10; IndieC1/ZM247: S9, T10). The N9S and S9N mutants had no change in MI-sensitivity. On the other hand, replacing glycine at residue 10 with threonine in K3016 reduced its MI sensitivity whereas introducing glycine at SP1 10 in place of threonine in IndieC1 and ZM247 significantly enhanced their MI sensitivity. Thus, the specific glycine residue 10 of SP1 in the HIV-1 subtype C viruses determined sensitivity towards BVM analogs. Conclusions We have identified an association of a specific glycine at position 10 of Gag-SP1 with an MI susceptible phenotype of HIV-1 subtype C viruses. Our findings have highlighted that HIV-1 subtype C viruses, which were inherently resistant to BVM, may also be similarly predisposed to exhibit a significant degree of resistance to second-generation BVM analogs. Our work has strongly suggested that genetic differences between HIV-1 subtypes may produce variable MI sensitivity that needs to be considered in the development of novel, potent, broadly-active MIs. Graphic abstract

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Section: Discussionmentioning

confidence: 99%

A single G10T polymorphism in HIV-1 subtype C Gag-SP1 regulates sensitivity to maturation inhibitors

Ghimire

Timilsina

et al. 2021

Retrovirology

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“…We believe that high-resolution structural data on a biologically relevant complex between gp41CT and MA in the context of a lipid bilayer can be crucial to this endeavor. As a key player in HIV-1 assembly and maturation, HIV-1 Gag and its individual domains emerged as attractive drug targets [182,183]. Recent advances in the development of potent CA and maturation (CA-SP1 cleavage site) inhibitors have demonstrated the therapeutic viability of Gag domains ( [182,183] and references therein).…”

Section: Gag-env-membrane Complex As a Therapeutic Targetmentioning

confidence: 99%

“…As a key player in HIV-1 assembly and maturation, HIV-1 Gag and its individual domains emerged as attractive drug targets [182,183]. Recent advances in the development of potent CA and maturation (CA-SP1 cleavage site) inhibitors have demonstrated the therapeutic viability of Gag domains ( [182,183] and references therein). Herein, we discussed three key features in viral assembly that could potentially serve as targets for anti-retroviral drugs: MA-membrane interface, MA trimer and gp41CT-MA interface.…”

Section: Gag-env-membrane Complex As a Therapeutic Targetmentioning

confidence: 99%

The Interplay between HIV-1 Gag Binding to the Plasma Membrane and Env Incorporation

Saad

2020

Viruses

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Advancement in drug therapies and patient care have drastically improved the mortality rates of HIV-1 infected individuals. Many of these therapies were developed or improved upon by using structure-based techniques, which underscore the importance of understanding essential mechanisms in the replication cycle of HIV-1 at the structural level. One such process which remains poorly understood is the incorporation of the envelope glycoprotein (Env) into budding virus particles. Assembly of HIV particles is initiated by targeting of the Gag polyproteins to the inner leaflet of the plasma membrane (PM), a process mediated by the N-terminally myristoylated matrix (MA) domain and phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2). There is strong evidence that formation of the Gag lattice on the PM is a prerequisite for the incorporation of Env into budding particles. It is also suggested that Env incorporation is mediated by an interaction between its cytoplasmic tail (gp41CT) and the MA domain of Gag. In this review, we highlight the latest developments and current efforts to understand the interplay between gp41CT, MA, and the membrane during assembly. Elucidation of the molecular determinants of Gag–Env–membrane interactions may help in the development of new antiviral therapeutic agents that inhibit particle assembly, Env incorporation and ultimately virus production.

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“…This is the first and only Food and Drug Administration (FDA)-approved anti-HIV drug targeting a host cellular protein. Due to the multiple roles capsid plays during infection, it has been exploited as a target for anti-retroviral compound screening [ 26 , 27 ]. A handful of compounds have been reported to bind capsid and disrupt infection, of which, PF-3450074 (PF74) and the Gilead compounds, GS-CA1 and GS-6207, are potent inhibitors [ 28 ].…”

Section: Introductionmentioning

confidence: 99%

Interactions of HIV-1 Capsid with Host Factors and Their Implications for Developing Novel Therapeutics

Zhuang

Torbett

2021

Viruses

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The Human Immunodeficiency Virus type 1 (HIV-1) virion contains a conical shell, termed capsid, encasing the viral RNA genome. After cellular entry of the virion, the capsid is released and ensures the protection and delivery of the HIV-1 genome to the host nucleus for integration. The capsid relies on many virus–host factor interactions which are regulated spatiotemporally throughout the course of infection. In this paper, we will review the current understanding of the highly dynamic HIV-1 capsid–host interplay during the early stages of viral replication, namely intracellular capsid trafficking after viral fusion, nuclear import, uncoating, and integration of the viral genome into host chromatin. Conventional anti-retroviral therapies primarily target HIV-1 enzymes. Insights of capsid structure have resulted in a first-in-class, long-acting capsid-targeting inhibitor, GS-6207 (Lenacapavir). This inhibitor binds at the interface between capsid protein subunits, a site known to bind host factors, interferes with capsid nuclear import, HIV particle assembly, and ordered assembly. Our review will highlight capsid structure, the host factors that interact with capsid, and high-throughput screening techniques, specifically genomic and proteomic approaches, that have been and can be used to identify host factors that interact with capsid. Better structural and mechanistic insights into the capsid–host factor interactions will significantly inform the understanding of HIV-1 pathogenesis and the development of capsid-centric antiretroviral therapeutics.

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Recent Advances in HIV-1 Gag Inhibitor Design and Development

Cited by 22 publications

References 149 publications

A single G10T polymorphism in HIV-1 subtype C Gag-SP1 regulates sensitivity to maturation inhibitors

A single G10T polymorphism in HIV-1 subtype C Gag-SP1 regulates sensitivity to maturation inhibitors

The Interplay between HIV-1 Gag Binding to the Plasma Membrane and Env Incorporation

Interactions of HIV-1 Capsid with Host Factors and Their Implications for Developing Novel Therapeutics

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