A Broad-Spectrum Antiviral Molecule, Protoporphyrin IX, Acts as a Moderator of HIV-1 Capsid Assembly by Targeting the Capsid Hexamer

Zhang, Da-Wei; Xie, Liangxu; Xu, Xiaojun; Li, Yimin; Xu, Xiaojun

doi:10.1128/spectrum.02663-22

Cited by 3 publications

(3 citation statements)

References 65 publications

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“…Biotinylated proteins were loaded onto the tips of SA sensors. The double reference subtracted method was conducted, as previously described, to determine three affinity constants: k on , k off , and K D ( Zhang et al, 2023 ).…”

Section: Methodsmentioning

confidence: 99%

Modulation of HIV-1 capsid multimerization by sennoside A and sennoside B via interaction with the NTD/CTD interface in capsid hexamer

Zhang,

Xu,

Zhou

et al. 2023

Front. Microbiol.

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Small molecules that bind to the pocket targeted by a peptide, termed capsid assembly inhibitor (CAI), have shown antiviral effects with unique mechanisms of action. We report the discovery of two natural compounds, sennoside A (SA) and sennoside B (SB), derived from medicinal plants that bind to this pocket in the C-terminal domain of capsid (CA CTD). Both SA and SB were identified via a drug-screening campaign that utilized a time-resolved fluorescence resonance energy transfer assay. They inhibited the HIV-1 CA CTD/CAI interaction at sub-micromolar concentrations of 0.18 μM and 0.08 μM, respectively. Mutation of key residues (including Tyr 169, Leu 211, Asn 183, and Glu 187) in the CA CTD decreased their binding affinity to the CA monomer, from 1.35-fold to 4.17-fold. Furthermore, both compounds induced CA assembly in vitro and bound directly to the CA hexamer, suggesting that they interact with CA beyond the CA CTD. Molecular docking showed that both compounds were bound to the N-terminal domain (NTD)/CTD interface between adjacent protomers within the CA hexamer. SA established a hydrogen-bonding network with residues N57, V59, Q63, K70, and N74 of CA1-NTD and Q179 of CA2-CTD. SB formed hydrogen bonds with the N53, N70, and N74 residues of CA1-NTD, and the A177and Q179 residues of CA2-CTD. Both compounds, acting as glue, can bring αH4 in the NTD and αH9 in the CTD of the NTD/CTD interface close to each other. Collectively, our research indicates that SA and SB, which enhance CA assembly, could serve as novel chemical tools to identify agents that modulate HIV-1 CA assembly. These natural compounds may potentially lead to the development of new antiviral therapies with unique mechanisms of action.

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Section: Methodsmentioning

confidence: 99%

Modulation of HIV-1 capsid multimerization by sennoside A and sennoside B via interaction with the NTD/CTD interface in capsid hexamer

Zhang,

Xu,

Zhou

et al. 2023

Front. Microbiol.

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“…Another HIV-1 complete replication assay incorporating an accessory protein, Vif, was reported [ 57 , 58 ]. A summary of medium-to-high throughput screening assays that have been used successfully in screening small molecular metabolites is provided in Figure 1 [ 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 ]. Developing these replication assays to represent all possible target sites in the HIV-1 genome will allow for rapid and unbiased screening of natural microbial products against various targets and save costs and time for hit identification [ 64 , 65 ].…”

Section: Advances In Antiviral Screening Assaysmentioning

confidence: 99%

“… A summary of medium and high throughput screening assays for small molecular metabolites with anti-HIV-1 activity [ 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 ]. …”

Section: Figurementioning

confidence: 99%

Developments in Exploring Fungal Secondary Metabolites as Antiviral Compounds and Advances in HIV-1 Inhibitor Screening Assays

Nzimande

Makhwitine

Mkhwanazi

et al. 2023

Viruses

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The emergence of drug-resistant Human Immunodeficiency Virus-1 strains against anti-HIV therapies in the clinical pipeline, and the persistence of HIV in cellular reservoirs remains a significant concern. Therefore, there is a continuous need to discover and develop new, safer, and effective drugs targeting novel sites to combat HIV-1. The fungal species are gaining increasing attention as alternative sources of anti-HIV compounds or immunomodulators that can escape the current barriers to cure. Despite the potential of the fungal kingdom as a source for diverse chemistries that can yield novel HIV therapies, there are few comprehensive reports on the progress made thus far in the search for fungal species with the capacity to produce anti-HIV compounds. This review provides insights into the recent research developments on natural products produced by fungal species, particularly fungal endophytes exhibiting immunomodulatory or anti-HIV activities. In this study, we first explore currently existing therapies for various HIV-1 target sites. Then we assess the various activity assays developed for gauging antiviral activity production from microbial sources since they are crucial in the early screening phases for discovering novel anti-HIV compounds. Finally, we explore fungal secondary metabolites compounds that have been characterized at the structural level and demonstrate their potential as inhibitors of various HIV-1 target sites.

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