The impact of Gag non-cleavage site mutations on HIV-1 viral fitness from integrative modelling and simulations

Samsudin, Firdaus; Gan, Samuel Ken‐En; Bond, Peter J.

doi:10.1016/j.csbj.2020.12.022

Cited by 9 publications

(10 citation statements)

References 87 publications

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“…Furthermore, targeting allosteric sites in microbial and viral proteins could drive function-crippling mutations through drug resistance mechanisms at the drug binding site. Evidence of allosteric sites are present in the HIV Gag protein where non-cleavage site mutations contributed to drug resistance associated protein fitness compensation 109,110 . These sites could be epitopes for intrabodies that in this example, either prevent drug-resistance or reduce protein fitness Such epitopes can be leveraged upon to dissociate already bound complexes or simply to increase dissociation for a modulation of the effects (e.g.…”

Section: In the Above Mentioned Example Of Steric Hindrances Of Trastuzumab And Pertuzumabmentioning

confidence: 99%

Sagacious Epitope Selection for Vaccines, and Both Antibody-Based Therapeutics and Diagnostics: Tips From Virology and Oncology<strong> </strong>

Gan¹,

Phua²,

Yeo³

2021

Preprint

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The target of an antibody plays a significant role in the success of antibody-based therapeutics and diagnostics, and to an extent, that of vaccine development. This importance is focussed on the target binding site – epitope, that sagacious epitope selection in a form of design thinking beyond traditional antigen selection using whole cell or whole protein immunisation can positively improve success. Intrinsic factors that can affect the functioning of resulting antibodies can be more easily selected for with purified recombinant protein production and peptide synthesis to display limited/selected epitopes. Many of these factors stem from the location of the epitope that can affect the accessibility of the antibody to the epitope at a cellular or molecular level, direct inhibition of target antigen activity, conservation of function despite escape mutations, and even non-competitive inhibition sites. Through the incorporation of novel computational methods for predicting antigen changes to model-informed drug design development, superior vaccines and antibody-based therapeutics or diagnostics can now be more easily designed, mitigating failures. With detailed examples, this review highlights the new opportunities, factors and methods of predicting antigenic changes for consideration in sagacious epitope selection.

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Section: In the Above Mentioned Example Of Steric Hindrances Of Trastuzumab And Pertuzumabmentioning

confidence: 99%

Sagacious Epitope Selection for Vaccines, and Both Antibody-Based Therapeutics and Diagnostics: Tips From Virology and Oncology<strong> </strong>

Gan¹,

Phua²,

Yeo³

2021

Preprint

Self Cite

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“…They found the resistance mutations interacted with me lipids, CypA, and Gag cleavage sites [51,52]. However, since PR was not included Gag modeling studies, it complicated the understanding of how the Gag non-cleav PI resistance mutations enabled PR resistance to PIs [51,52]. It is proposed that at each step in the cleavage of a Gag polyprotein substrate, there is a rate enhancement over the cleavage of the Gag protein substrate, and that is indicated by the relative lengths of the association and disassociation arrows (Figure 9): (1) the Gag polyprotein substrates have long unstructured linkers containing the cleavage site; (2) the ability of the Gag polyprotein substrates to form a substrate-clamp can prevent the bound PR dimer from disassociating from the polyprotein substrate until PR cleaved the Gag polyprotein substrate, irreversibly breaking the substrate-clamp.…”

Section: Interaction Energy Scores Between Pr and Substrates And Substrate Subdomainsmentioning

confidence: 99%

Section: Interaction Energy Scores Between Pr and Substrates And Substrate Subdomainsmentioning

confidence: 99%

“…Several other research groups have also carried out modeling studies of HIV-1 Gag to gain insight into the mechanism of Gag non-cleavage site PI resistance mutations including H219Q [51,52]. They found the resistance mutations interacted with membrane lipids, CypA, and Gag cleavage sites [51,52]. However, since PR was not included in those Gag modeling studies, it complicated the understanding of how the Gag non-cleavage site PI resistance mutations enabled PR resistance to PIs [51,52].…”

Section: Interaction Energy Scores Between Pr and Substrates And Substrate Subdomainsmentioning

confidence: 99%

“…They found the resistance mutations interacted with membrane lipids, CypA, and Gag cleavage sites [51,52]. However, since PR was not included in those Gag modeling studies, it complicated the understanding of how the Gag non-cleavage site PI resistance mutations enabled PR resistance to PIs [51,52].…”

Section: Interaction Energy Scores Between Pr and Substrates And Substrate Subdomainsmentioning

confidence: 99%

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HIV-1 Gag Non-Cleavage Site PI Resistance Mutations Stabilize Protease/Gag Substrate Complexes In Silico via a Substrate-Clamp

Laco

2021

BioChem

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HIV-1 protease active site inhibitors are a key part of antiretroviral therapy, though resistance can evolve rendering therapy ineffective. Protease inhibitor resistance typically starts with primary mutations around the active site, which reduces inhibitor binding, protease affinity for substrate cleavage site residues P4-P4′, and viral replication. This is often followed by secondary mutations in the protease substrate-grooves which restore viral replication by increasing protease affinity for cleavage site residues P12-P5/P5′-P12′, while maintaining resistance. However, mutations in Gag alone can also result in resistance. The Gag resistance mutations can occur in cleavage sites (P12-P12′) to increase PR binding, as well as at non-cleavage sites. Here we show in silico that Gag non-cleavage site protease inhibitor resistance mutations can stabilize protease binding to Gag cleavage sites which contain structured subdomains on both sides: SP1/NC, SP2/p6, and MA/CA. The Gag non-cleavage site resistance mutations coordinated a network of H-bond interactions between the adjacent structured subdomains of the Gag substrates to form a substrate-clamp around the protease bound to cleavage site residues P12-P12′. The substrate-clamp likely slows protease disassociation from the substrate, restoring the cleavage rate in the presence of the inhibitor. Native Gag substrates can also form somewhat weaker substrate-clamps. This explains the 350-fold slower cleavage rate for the Gag CA/SP1 cleavage site in that the CA-SP1 substrate lacks structured subdomains on both sides of the cleavage site, and so cannot form a substrate-clamp around the PR.

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Integrative structural biology of HIV-1 capsid protein assemblies: combining experiment and computation

Perilla

Hadden‐Perilla

Gronenborn

et al. 2021

Current Opinion in Virology

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The impact of Gag non-cleavage site mutations on HIV-1 viral fitness from integrative modelling and simulations

Cited by 9 publications

References 87 publications

Sagacious Epitope Selection for Vaccines, and Both Antibody-Based Therapeutics and Diagnostics: Tips From Virology and Oncology<strong> </strong>

Sagacious Epitope Selection for Vaccines, and Both Antibody-Based Therapeutics and Diagnostics: Tips From Virology and Oncology<strong> </strong>

HIV-1 Gag Non-Cleavage Site PI Resistance Mutations Stabilize Protease/Gag Substrate Complexes In Silico via a Substrate-Clamp

Integrative structural biology of HIV-1 capsid protein assemblies: combining experiment and computation

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