Discoveries and developments of CXCR4-targeted HIV-1 entry inhibitors

Abstract

The chemokine receptor CXCR4 is required for the entry of human immunodeficiency virus type 1 (HIV-1) into target cells and its expression correlates with more profound pathogenicity, rapid progression to acquired immunodeficiency syndrome (AIDS), and greater AIDS-related mortality. There is still no cure for AIDS and no method for preventing or eradicating HIV-1 infection. HIV-1 entry begins with the interaction of the viral envelope glycoprotein gp120 and the primary receptor CD4, and subsequently with the coreceptors, CCR5 or CXCR4, on the host cells. Blocking the interaction of HIV-1 and its coreceptors is therefore a promising strategy for developing new HIV-1 entry inhibitors. This approach has a dual benefit, as it prevents HIV-1 infection and progression while also targeting the reservoirs of HIV-1 infected, coreceptor positive macrophages and memory T cells. To date, multiple classes of CXCR4-targeted anti-HIV-1 inhibitors have been discovered and are now at different preclinical and clinical stages. In this review, we highlight the studies of CXCR4-targeted small-molecule and peptide HIV-1 entry inhibitors discovered during the last two decades and provide a reference for further potential HIV-1 exploration in the future. Impact statement This minireview summarized the current progress in the identification of CXCR4-targeted HIV-1-entry inhibitors based on discovery/developmental approaches. It also provided a discussion of the inhibitor structural features, antiviral activities, and pharmacological properties. Unlike other reviews on anti-HIV-1 drug development, which have generally emphasized inhibitors that target intracellular viral replication and host genomic integration, this review focused on the drug discovery approaches taken to develop viral-entry inhibitors aimed at disturbing the initial step of viral interaction with uninfected host cells and preventing the subsequent viral replication/genomic integration. This review amalgamated recently published and important work on bivalent CXCR4-targeted anti-HIV-1-entry candidates/conjugates, discussed the research challenges faced in developing drugs to prevent and eradicate HIV-1 infection, and provided a perspective on strategies that can lead to future drug discoveries. The findings and strategies summarized in this review will be of interest to investigators throughout the microbiological, pharmaceutical, and translational research communities.

Role of CXCR4 in the progression and therapy of acute leukaemia

“…4,17 Therefore, increasing efforts have been made to develop new CXCR4 antagonists to control HIV infection (reviewed by Zhang et al). 18 CXCR4 also plays important roles in the development, invasion, angiogenesis, epithelial-mesenchymal transition and maintenance of stemness of tumour cells, [19][20][21][22][23] and targeting CXCR4 is a potential therapeutic strategy for treating malignant tumours. [24][25][26] Acute leukaemia (AL) includes acute myeloid leukaemia (AML) and acute lymphoblastic leukaemia (ALL).…”

HIV-1 Entry and Membrane Fusion Inhibitors

“…It binds to the cavity within the transmembrane domain of CCR5 and disrupts gp120 binding as a direct competitor [ 83 ]. Entry inhibitors targeting CXCR4, such as AMD3100, AMD3465, and AMD070, also show an inhibitory potency at the nM level [ 135 , 136 , 137 , 138 ], but they have yet to be approved for clinical use.…”

Co-receptor signaling in the pathogenesis of neuroHIV

“…Targeting CXCR4 with specific agonists or molecules that promote the internalization and sequestration has not been as widely explored as for CCR5, owing in part to the physiological requirements for CXCR4 binding. However, there has been some progress in finding drugs that can induce signaling while preventing viral binding [ 43 , 331 ].…”

“…There are a number of reasons co-receptors are difficult to target, including the ability of HIV to utilize multiple different conformations [ 293 , 300 ] and interference of therapeutics with homeostatic signaling leading to off-target effects [ 43 , 556 ]. The latter is particularly problematic for targeting CXCR4, as the essential function of CXCR4 in numerous homeostatic processes precludes the development of inhibitors targeting this receptor [ 43 , 557 ]. Targeting CCR5 and CXCR4 are both associated with their own unique set of challenges; therefore, we will address these challenges and the current state of therapeutics separately.…”

“…However, these efforts continue to be hindered by an incomplete understanding of how co-receptor signaling and specific co-receptor conformations contribute to viral infection. Blocking co-receptor activity affects many more processes than just HIV neuropathogenesis, and co-receptor inhibitors often have unwanted side-effects in regard to disruption of homeostatic function [ 42 , 43 ], further complicating the development of targeted therapeutics for these receptors. There is currently only one FDA-approved antiretroviral targeting an HIV co-receptor, the CCR5 inhibitor Maraviroc, and its efficacy often decreases with disease progression due to mutations that interfere with gp120 binding to CCR5 [ 37 , 44 , 45 ].…”