Current HIV entry inhibitors target the binding of the viral envelope glycoprotein gp120 to cellular CD4 and co-receptors, or block a late stage of the fusogenic activation of adjacent gp41. New targets are suggested by the role of cell surface protein disulfide isomerase (PDI), which attaches to the primary receptor CD4 close to the gp120-binding site. This could enable PDI to reduce gp120 disulfide bonds, which triggers the major conformational changes in gp120 and gp41 required for virus entry. Inhibiting cell surface PDI prevents HIV-1 entry. The new potential targets outlined are PDI activity as well as the sites of PDI-CD4 and PDI-gp120 interaction.
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Mechanism of HIV-1 entry
It has long been known that entry of HIV-1 into human lymphoid cells requires the cooperation of the viral envelope glycoproteins gp120 and gp41, and of two host-cell proteins, the primary receptor CD4 and a chemokine co-receptor (CCR5 or CXCR4) [1]. More recently a third cell-surface protein was found to play a critical role in HIV-1 entry: the oxidoreductase protein disulfide isomerase (PDI) [2, 3, 4, 5, 6]. Gp120 attaches the virus to the cell by binding to CD4. It was found that CD4 also
Evidence for the participation of PDI in HIV-1 entry
Inhibition of the activity of PDI at the surface of target cells prevents the activation of gp41 [6], the entry of HIV-1 strains into target cells [4] (Figure 3), and envelope-mediated cell-cell fusion [3, 4]. The following facts and experimental data explain how surface PDI might exert such a critical role. (1) At the cell surface PDI acts as a reductase that cleaves disulfide bonds of proteins attached to the cell, whereas inside the cell PDI forms disulfide bonds in nascent proteins (Figure 4
Inhibitors of HIV-1 entry in use or under development
The search for agents that prevent HIV-1 entry has focused on blocking (a) the interaction of gp120 with the cellular receptor CD4, (b) the secondary interaction of gp120 with cellular co-receptors CCR5 or CXCR4 and (c) the formation of the six-helix bundle of fusion-active gp41. The first two approaches led to promising inhibitors that are under active clinical investigation. The third led to a potent inhibitor of HIV-1 entry that has been approved by the FDA for the treatment of AIDS
New targets uncovered by the participation of PDI in virus entry
The involvement of PDI in HIV-1 entry identifies three new targets (Figure 5) that could be exploited to prevent HIV-1 entry: (1) the activity of surface PDI; (2) the binding of PDI to CD4; (3) the access of CD4-bound PDI to gp120 disulfide bonds. All three processes are essential for infection and differ from those used in past drug developments (Figure 5).
Summary
Conformational changes in receptor-bound gp120 profound enough to activate virus-cell fusion can be initiated by the reduction of structure-stabilizing disulfide bonds, carried out by the receptor-associated enzyme PDI. This view suggests three novel targets for anti-HIV-1 drug development. Inhibiting the activity of surface PDI, the first potential target, is not a favored option because the enzyme serves other physiological functions at the cell surface. The sites of PDI-CD4 and PDI-gp120
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It can be seen from Table 1 that most drugs in HAART target the HIV-1 reverse transcriptase and protease to prevent viral replication in cells. Only four HIV-1 EIs, the fusion inhibitor enfuvirtide (T-20), the CCR5 antagonist maraviroc, the attachment inhibitor fostemsavir, and the post-attachment inhibitor ibalizumab-uiyk, have been used in HAART (De Clercq, 2005; Ryser and Fluckiger, 2005; Este and Telenti, 2007; Rusconi et al., 2007; Adamson and Freed, 2010; Chahine, 2021; Kozal et al., 2020). Enfuvirtide presents a 36-residue peptide that binds to the gp41 protein and hinders the structural rearrangements necessary for virus-cell membrane fusion (Matthews et al., 2004).
Highly active antiretroviral therapy currently used for HIV/AIDS has significantly increased the life expectancy of HIV-infected individuals. It has also improved the quality of life, reduced mortality, and decreased the incidence of AIDS and HIV-related conditions. Currently, however, affected individuals are typically on a lifetime course of several therapeutic drugs, all with the potential for associated toxicity and emergence of resistance. This calls for development of novel, potent, and broad anti-HIV agents able to stop the spread of HIV/AIDS. Significant progress has been made toward identification of anti-HIV-1 broadly neutralizing antibodies (bNAbs). However, antibody-based drugs are costly to produce and store. Administration (by injection only) and other obstacles limit clinical use. In recent years, several highly promising small-molecule HIV-1 entry inhibitors targeting the epitopes of bNAbs have been developed. These newly developed compounds are the focus of the present article.
The COVID-19 pandemic caused by the novel SARS-CoV-2 virus has caused havoc across the entire world. Even though several COVID-19 vaccines are currently in distribution worldwide, with others in the pipeline, treatment modalities lag behind. Accordingly, researchers have been working hard to understand the nature of the virus, its mutant strains, and the pathogenesis of the disease in order to uncover possible drug targets and effective therapeutic agents. As the research continues, we now know the genome structure, epidemiological and clinical features, and pathogenic mechanism of SARS-CoV-2. Here, we summarized the potential therapeutic targets involved in the life cycle of the virus. On the basis of these targets, small-molecule prophylactic and therapeutic agents have been or are being developed for prevention and treatment of SARS-CoV-2 infection.
Disulfide bond formation is catalyzed by the protein disulfide Isomerases (PDI) family. This is a critical step in protein folding which occurs within the endoplasmic reticulum. PDIA4, as a member of the PDI family, can cause the adjustment of αIIβ 3 affinities which activate platelet and promote thrombosis formation. Endoplasmic reticulum response is triggered by accumulation of abnormal folding proteins concomitant with increasing PDIA4 expression. Besides, current researches indicate that activated platelets and ERS response affect tumor progression. And PDIA4, as previous reported, also participates in tumor progression by affecting cell apoptosis and DNA repair machinery without specific mechanisms revealed.Therefore, PDI inhibitor might possess great potential value in against tumor progression. In this review, we summarize information on PDIA4 including its the basic characteristics and its implication on tumor.
2020, Animal Biotechnology: Models in Discovery and Translation
Acquired immune deficiency syndrome (AIDS) is the terminal stage of human immunodeficiency virus (HIV) infections. HIV is one of the dreaded infectious diseases of the late 20th century. This chapter provides information about the history, discovery, epidemiology, and replication of HIV. Anti-HIV drugs and novel anti-HIV drug targets for development of new drugs are also discussed.
The utilization of bioactive peptides in the development of highly selective and potent pharmacological agents for the disruption of protein–protein interactions is appealing for drug discovery. It is known that HIV-1 entry into a host cell is through a fusion process that is mediated by the trimeric viral glycoprotein gp120/41, which is derived from gp160 through proteolytic processing. Peptides derived from the HIV gp41 C-terminus have proven to be potent in inhibiting the fusion process. These peptides bind tightly to the hydrophobic pocket on the gp-41 N-terminus, which was previously identified as a potential inhibitor binding site. In this study, we introduce modified 23-residue C-peptides, 3 and 4, bearing a sulfono-γ-AA residue substitution and hydrocarbon stapling, respectively, which were developed for HIV-1 gp-41 N-terminus binding. Intriguingly, both 3 and 4 were capable of inhibiting envelope-mediated membrane fusion in cell–cell fusion assays at nanomolar potency. Our study reveals that sulfono-γ-AA modified peptides could be used for the development of more potent anti-HIV agents.
HUGUES J-P.RYSER Hugues Ryser received his MD and Dr. Med. from the University of Berne, Switzerland. In 1972 he became professor of Pathology and Pharmacology at Boston University, where he is now Professor Emeritus. His laboratory developed drug-macromolecular conjugates that release anti-cancer drugs inside cells. The observation that disulfide bonds in drug conjugates are cleaved upon attachment to cells led to the finding that some gp120 disulfide bonds are reduced upon binding of HIV-1 to its surface receptor.
RUDOLF FLÜCKIGER Rudolf Flückiger is an instructor at the Harvard Medical School, Boston. He studied biochemistry at the ETH-Zürich, Switzerland, and received his PhD and venia docendi from the University Basel. He joined the Harvard Research Community in 1989. There he developed PQQ inhibitory compounds and designed anticancer agents that target translation initiation.
