Investigating the Unique Mechanism of Action of CADA Analogs for Down-Modulating CD4, Sortilin, and ACE2
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Authors
Islam, Md Azizul
Issue Date
2023
Type
Dissertation
Language
Keywords
2D IR , CADA , CD4 , Cotranslational Translocation , Sec61 , Signal Peptide
Alternative Title
Abstract
The small molecule cyclotriazadisulfonamide (CADA) has been found to inhibit the replication of human immunodeficiency virus (HIV) and human herpesvirus type 7 in cell cultures. It works by down-modulating human CD4 (hCD4) and blocking co-translational translocation of the nascent protein across the endoplasmic reticulum (ER) membrane, which prevents the entry of HIV virus into target cells. The key amino acid residues that are critical for sensitivity to CADA are glutamine (Q-15) and proline (P-20) in the hCD4 signal peptide (SP). It has been proposed that CK147 may bind with the hCD4 signal peptide through a dipole-dipole interaction between the N,N-dimethylaminobenzenesulfonyl side-arm of CK147 and the amide side chain of glutamine (Q-15) of hCD4 SP, forming a folded conformation similar to the transitory state during translocation. It was also proposed that CK147 might interact with the CD4 signal peptide through hydrogen bonding between the sulfonamide oxygen atom of one of the side arms of CK147 and the hydrogen atom of the amide side chain of the glutamine (Q-15) of the CD4 SP.The aim of this research was to synthesize deuterium-labeled CADA analogs and signal peptides to determine the structure of the complex formed between the small molecule and the hCD4 signal peptide, as well as to study the interactions between CADA analog (CK147) and hCD4 SP through two-dimensional infrared spectroscopy (2D IR). Another aim was to synthesize a library of CADA analogs with enhanced potency and selectivity towards the down-modulation of several proteins (CD4, ACE2, sortilin) with the establishment of a pharmacokinetic profile of various biologically active CADA analogs. To achieve these goals, deuterium-labeled CADA analogs (CK147 and TL020) and several signal peptides (hCD4, mCD4, Q19A mCD4, Q16A Q19A mCD4) were synthesized. Also, a library of new CADA analogs was synthesized with modified arylsulfonamide side-arms to better understand the interaction of CADA analogs with SPs. In order to explore the selectivity of CADA analogs towards different signal peptides, a new class of CADA analogs was synthesized by modifying the isobutyl head group. At last, a set of potential bioactive small molecules, TL020, TL027, and VGD020 have been uncovered. These promising compounds have the ability to reduce the expression of angiotensin-converting enzyme-2 (ACE2), suggesting a potential therapeutics to effectively alleviate SARS-CoV-2 infection.