Design and synthesis of small molecule-sulfotyrosine mimetics that inhibit HIV-1 entry

Abstract

In the absence of a cure or vaccine for HIV/AIDS, small molecule inhibitors remain an attractive choice for antiviral therapeutics. Recent structural and functional studies of the HIV-1 surface envelope glycoprotein gp120 have revealed sites of vulnerability that can be targeted by small molecule and peptide inhibitors, thereby inhibiting HIV-1 infection. Here we describe a series of small molecule entry inhibitors that were designed to mimic the sulfated N-terminal peptide of the HIV-1 coreceptor CCR5. From a panel of hydrazonothiazolyl pyrazolinones, we demonstrate that compounds containing naphthyl di- and tri-sulfonic acids inhibit HIV-1 infection in single round infectivity assays with the disulfonic acids being the most potent. Molecular docking supports the observed structure activity relationship, and SPR confirmed binding to gp120. In infectivity assays treatment with a representative naphthyl disulfonate and a disulfated CCR5 N-terminus peptide results in competitive inhibition, with combination indices >2. In total this work shows that gp120 and HIV-1 infection can be inhibited by small molecules that mimic the function of, and are competitive with the natural sulfated CCR5 N-terminus.

HIV‐1 Entry Inhibitors: A Review of Experimental and Computational Studies

“…The disulfonic acids were the most potent compounds. Surface plasmon resonance tests showed that these compounds bind to trimeric gp120 and docking studies also verified the structure–activity relationship results …”

“…Surface plasmon resonance tests showed that these compounds bind to trimeric gp120 and docking studies also verified the structure-activity relationship results. [31] Curreli et al in a continuous work reported two potent compounds, NBD-14088 and NBD-14107 (7 and 8, respectively; Figure 5), as CD4 mimic entry inhibitors that target the Phe43 cavity of HIV gp120. These compounds had better anti-HIV-1 effects and ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties than the potent HIV-1 attachment inhibitor Temsavir 9 (BMS-626529; Figure 5).…”

“…Unlike cyclam compounds, non-cyclam antagonists have better bioavailability. AMD070 (31) was tested in human cases which have shown X4-tropic virus in their plasma. It had good bioavailability and anti-HIV-1 potency.…”

Angiotensin‐converting enzyme 2: The old door for new severe acute respiratory syndrome coronavirus 2 infection

“…Also, peptide mimetics or smallmolecule inhibitors have been developed to block viral entry or to suppress viral infection, and similar strategies can also be applied to COVID-19. 142 Particularly, targeted immunotherapy using smallmolecule inhibitors to prevent cytokine storm syndrome has emerged as a potent treatment option for COVID-19 patients. 143 The ultimate objective of targeted immunotherapy is to optimize the cytokine productions and inflammatory responses upon viral infections.…”