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Development and functionality of new classes of small macrocyclic HIV-1 Env inactivators
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Development and functionality of new classes of small macrocyclic HIV-1 Env inactivators

Aicha Bendia
Master of Science (M.S.), Drexel University
May 2022
DOI:
https://doi.org/10.17918/00001182
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Abstract

HIV (Viruses)
HIV-1 entry to the cell is a key step for infection. Entry remains a critical multi-stage process that results in conformational change in the HIV envelope protein, which leads to membrane fusion. The Chaiken Lab has previously developed peptide triazoles (PTs) and their cyclic counterparts (cPTs) that function as dual antagonists targeting the gp120 subunits of the HIV-1 Envelope trimer. Moreover, this class of entry inhibitors is able to block the virus envelope entry to the cell, cause shedding, and envelope inactivation. The entry inhibition path is a crucial key for therapeutic discovery and development, specially that no vaccine has been attained yet to battle HIV-1 infection. This study is to investigate a lead cPT's pharmacophore to improve the potency against HIV-1 infection. Four boronic compounds were selected to modify the peptide thiophene group, to gain information about the peptide structure sensitivity and to test potency enhancement. Derivatives were designed and synthesized via microwave assisted solid phase peptide synthesis, purified using RP-HPLC system, and their binding activities was measured via SPR. The infection inhibition property was measure as well to be compared to values predicted by a QSAR model. Despite the synthetic challenges, four new cPTs were generated and all are active in binding to HIV-1 gp120 Env, one showed an excellent binding activity compared to the preceding generation.

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