Potentiation of Drug Toxicity through Virus Latency Reversal Promotes Preferential Elimination of HIV Infected Cells

Thanh Tung Truong; Manuel Hayn; Camilla Kaas Frich; Lia-Raluca Olari; Lucy Kate Ladefoged; Morten Tobias Jarlstad Olesen; Josefine H. Jakobsen; Cherie K. Lunabjerg-Vestergaard; Birgit Schiøtt; Jan Münch; Alexander N. Zelikin

doi:10.1002/adtp.202200113

Potentiation of Drug Toxicity through Virus Latency Reversal Promotes Preferential Elimination of HIV Infected Cells

Thanh Tung Truong, Manuel Hayn, Camilla Kaas Frich, Lia-Raluca Olari, Lucy Kate Ladefoged, Morten Tobias Jarlstad Olesen, Josefine H. Jakobsen, Cherie K. Lunabjerg-Vestergaard, Birgit Schiøtt, Jan Münch^*, Alexander N. Zelikin^*

^*Corresponding author for this work

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Abstract

Eliminating latently infected cells is a highly challenging, indispensable step toward the cure for HIV/AIDS. Hypothesis put forward herein is that the unique HIV protease cut site (Phe-Pro) can be reconstructed using a potent inhibitor of tubulin polymerization, monomethyl auristatin F (MMAF), which features Phe at its C-terminus. This presents opportunities to design prodrugs that are specifically activated by the HIV protease. To this end, a series of MMAF derivatives is synthesized and evaluated in cell culture using latently HIV-infected cells. The cytotoxicity of compounds is indeed enhanced upon latency reversal by up to 11-fold. As a result, in a mixed cell population, nanomolar concentrations of the lead compounds depletes predominantly the HIV-infected cells and in doing so markedly enriches the pool of the uninfected cells. Affinity of the lead compounds to the viral protease is validated computationally and experimentally but despite expectations, the mechanism of action of the synthesized toxins is shown to be independent from the enzymatic activity of the HIV protease.

Original language	English
Article number	2200113
Journal	Advanced Therapeutics
Volume	5
Issue	11
Number of pages	7
ISSN	2366-3987
DOIs	https://doi.org/10.1002/adtp.202200113
Publication status	Published - Nov 2022

Keywords

drug design
HIV latency
latency reversal

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Advanced Therapeutics - 2022 - Truong - Potentiation of Drug Toxicity through Virus Latency Reversal Promotes PreferentialFinal published version, 1.33 MBLicence: CC BY-NC-ND

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Truong, T. T., Hayn, M., Frich, C. K., Olari, L.-R., Ladefoged, L. K., Olesen, M. T. J., Jakobsen, J. H., Lunabjerg-Vestergaard, C. K., Schiøtt, B., Münch, J., & Zelikin, A. N. (2022). Potentiation of Drug Toxicity through Virus Latency Reversal Promotes Preferential Elimination of HIV Infected Cells. Advanced Therapeutics, 5(11), Article 2200113. https://doi.org/10.1002/adtp.202200113

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title = "Potentiation of Drug Toxicity through Virus Latency Reversal Promotes Preferential Elimination of HIV Infected Cells",

abstract = "Eliminating latently infected cells is a highly challenging, indispensable step toward the cure for HIV/AIDS. Hypothesis put forward herein is that the unique HIV protease cut site (Phe-Pro) can be reconstructed using a potent inhibitor of tubulin polymerization, monomethyl auristatin F (MMAF), which features Phe at its C-terminus. This presents opportunities to design prodrugs that are specifically activated by the HIV protease. To this end, a series of MMAF derivatives is synthesized and evaluated in cell culture using latently HIV-infected cells. The cytotoxicity of compounds is indeed enhanced upon latency reversal by up to 11-fold. As a result, in a mixed cell population, nanomolar concentrations of the lead compounds depletes predominantly the HIV-infected cells and in doing so markedly enriches the pool of the uninfected cells. Affinity of the lead compounds to the viral protease is validated computationally and experimentally but despite expectations, the mechanism of action of the synthesized toxins is shown to be independent from the enzymatic activity of the HIV protease.",

keywords = "drug design, HIV latency, latency reversal",

author = "Truong, {Thanh Tung} and Manuel Hayn and Frich, {Camilla Kaas} and Lia-Raluca Olari and Ladefoged, {Lucy Kate} and Olesen, {Morten Tobias Jarlstad} and Jakobsen, {Josefine H.} and Lunabjerg-Vestergaard, {Cherie K.} and Birgit Schi{\o}tt and Jan M{\"u}nch and Zelikin, {Alexander N.}",

year = "2022",

month = nov,

doi = "10.1002/adtp.202200113",

language = "English",

volume = "5",

journal = "Advanced Therapeutics",

issn = "2366-3987",

publisher = "Wiley-Blackwell Publishing Ltd",

number = "11",

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Potentiation of Drug Toxicity through Virus Latency Reversal Promotes Preferential Elimination of HIV Infected Cells. / Truong, Thanh Tung; Hayn, Manuel; Frich, Camilla Kaas et al.
In: Advanced Therapeutics, Vol. 5, No. 11, 2200113, 11.2022.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

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T1 - Potentiation of Drug Toxicity through Virus Latency Reversal Promotes Preferential Elimination of HIV Infected Cells

AU - Truong, Thanh Tung

AU - Hayn, Manuel

AU - Frich, Camilla Kaas

AU - Olari, Lia-Raluca

AU - Ladefoged, Lucy Kate

AU - Olesen, Morten Tobias Jarlstad

AU - Jakobsen, Josefine H.

AU - Lunabjerg-Vestergaard, Cherie K.

AU - Schiøtt, Birgit

AU - Münch, Jan

AU - Zelikin, Alexander N.

PY - 2022/11

Y1 - 2022/11

N2 - Eliminating latently infected cells is a highly challenging, indispensable step toward the cure for HIV/AIDS. Hypothesis put forward herein is that the unique HIV protease cut site (Phe-Pro) can be reconstructed using a potent inhibitor of tubulin polymerization, monomethyl auristatin F (MMAF), which features Phe at its C-terminus. This presents opportunities to design prodrugs that are specifically activated by the HIV protease. To this end, a series of MMAF derivatives is synthesized and evaluated in cell culture using latently HIV-infected cells. The cytotoxicity of compounds is indeed enhanced upon latency reversal by up to 11-fold. As a result, in a mixed cell population, nanomolar concentrations of the lead compounds depletes predominantly the HIV-infected cells and in doing so markedly enriches the pool of the uninfected cells. Affinity of the lead compounds to the viral protease is validated computationally and experimentally but despite expectations, the mechanism of action of the synthesized toxins is shown to be independent from the enzymatic activity of the HIV protease.

AB - Eliminating latently infected cells is a highly challenging, indispensable step toward the cure for HIV/AIDS. Hypothesis put forward herein is that the unique HIV protease cut site (Phe-Pro) can be reconstructed using a potent inhibitor of tubulin polymerization, monomethyl auristatin F (MMAF), which features Phe at its C-terminus. This presents opportunities to design prodrugs that are specifically activated by the HIV protease. To this end, a series of MMAF derivatives is synthesized and evaluated in cell culture using latently HIV-infected cells. The cytotoxicity of compounds is indeed enhanced upon latency reversal by up to 11-fold. As a result, in a mixed cell population, nanomolar concentrations of the lead compounds depletes predominantly the HIV-infected cells and in doing so markedly enriches the pool of the uninfected cells. Affinity of the lead compounds to the viral protease is validated computationally and experimentally but despite expectations, the mechanism of action of the synthesized toxins is shown to be independent from the enzymatic activity of the HIV protease.

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KW - HIV latency

KW - latency reversal

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DO - 10.1002/adtp.202200113

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ER -

Potentiation of Drug Toxicity through Virus Latency Reversal Promotes Preferential Elimination of HIV Infected Cells

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