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In preclinical studies, GST-HG141, a novel hepatitis B virus (HBV) capsid assembly modulator displayed potent anti-HBV activity in vitro and strong efficacy in HBV animal models. A randomized, double-blind, ascending phase 1b trial assessed the pharmacokinetics, safety, and efficacy of GST-HG141 in chronic hepatitis B (CHB) individuals. Thirty treatment-naïve CHB patients were enrolled in three cohorts (25, 50, and 100 mg twice orally after meals daily) over 28 days, with 10 subjects per cohort (8:2 ratio for GST-HG141 and placebo). Dose-related safety and tolerability, pharmacokinetic profiles, and drug responses were evaluated. GST-HG141 exhibited a generally favorable safety profile across all doses with predominantly mild adverse reactions, including three cases of grade 1 transaminase elevations. Significant reductions in HBV DNA and pregenomic RNA (pgRNA) levels were observed across all doses of (25, 50, and 100 mg of GST-HG141, twice-daily) after 28 days of treatment. Pharmacokinetic analysis showed a consistent linear trend in GST-HG141 concentrations, with mean trough concentrations ranging from 75 to 240 ng/mL. These concentrations adequately covered the protein binding-adjusted EC50 (16.89 ng/mL) by factors of 4.4, 11.1, and 14.6 for doses of 25, 50, and 100 mg, respectively. Our study demonstrated GST-HG141’s well-tolerated profile up to 100 mg over 4 weeks, alongside robust antiviral activity in CHB patients, supporting its progression into further clinical investigation for CHB management.

Type 1 interferon suppresses viral replication by upregulating the expression of interferon-stimulated genes with diverse antiviral properties 1 . The replication of human immunodeficiency virus type 1 (HIV-1) is naturally inhibited by interferon, with the steps between viral entry and chromosomal integration of viral DNA being notably susceptible 2 – 5 . The interferon-stimulated gene myxovirus resistance 2 has been defined as an effective postentry inhibitor of HIV-1, but is only partially responsible for interferon’s suppressive effect 6 – 8 . Using small interfering RNA-based library screening in interferon-α-treated cells, we sought to characterize further interferon-stimulated genes that target the pre-integration phases of HIV-1 infection, and identified human tripartite-containing motif 5α (TRIM5α) as a potent anti-HIV-1 restriction factor. Human TRIM5α, in contrast with many nonhuman orthologues, has not generally been ascribed substantial HIV-1 inhibitory function, a finding attributed to ineffective recognition of cytoplasmic viral capsids by TRIM5α 2 , 9 , 10 . Here, we demonstrate that interferon-α-mediated stimulation of the immunoproteasome, a proteasome isoform mainly present in immune cells and distinguished from the constitutive proteasome by virtue of its different catalytic β-subunits, as well as the proteasome activator 28 regulatory complex 11 – 13 , and the associated accelerated turnover of TRIM5α underpin the reprogramming of human TRIM5α for effective capsid-dependent inhibition of HIV-1 DNA synthesis and infection. These observations identify a mechanism for regulating human TRIM5α antiviral function in human cells and rationalize how TRIM5α participates in the immune control of HIV-1 infection. Using a small interfering RNA-based library screening in interferon-treated cells, the authors identified human tripartite-containing motif 5α as potent restriction factor that inhibits HIV-1 DNA synthesis and infection in a capsid- and immunoproteasome-dependent manner.

People living with HIV (PLWH) have expressed concern about the life-long burden and stigma associated with taking pills daily and can experience medication fatigue that might lead to suboptimal treatment adherence and the emergence of drug-resistant viral variants, thereby limiting future treatment options 1 – 3 . As such, there is strong interest in long-acting antiretroviral (ARV) agents that can be administered less frequently 4 . Herein, we report GS-CA1, a new archetypal small-molecule HIV capsid inhibitor with exceptional potency against HIV-2 and all major HIV-1 types, including viral variants resistant to the ARVs currently in clinical use. Mechanism-of-action studies indicate that GS-CA1 binds directly to the HIV-1 capsid and interferes with capsid-mediated nuclear import of viral DNA, HIV particle production and ordered capsid assembly. GS-CA1 selects in vitro for unfit GS-CA1-resistant capsid variants that remain fully susceptible to other classes of ARVs. Its high metabolic stability and low solubility enabled sustained drug release in mice following a single subcutaneous dosing. GS-CA1 showed high antiviral efficacy as a long-acting injectable monotherapy in a humanized mouse model of HIV-1 infection, outperforming long-acting rilpivirine. Collectively, these results demonstrate the potential of ultrapotent capsid inhibitors as new long-acting agents for the treatment of HIV-1 infection. A new compound that inhibits HIV capsid assembly and nuclear transport functions offers potential as a long-acting antiretroviral.

Size-selective pores in the HIV-1 capsid hexamer recruit nucleotides, thereby allowing reverse transcription to take place inside the capsid. Capsid pores key to HIV-1 proliferation Recent work has suggested that HIV-1 evades innate DNA sensors such as cGAS by enclosing the viral genome inside a protective protein shell, the capsid. If the virus is to establish infection, however, it needs to be able to synthesize DNA. Leo James and colleagues show that HIV-1 sustains DNA synthesis inside the capsid by importing nucleotides through dynamic size-selective pores. The authors use structural, biophysical and virological methods to characterize these pores and find that they are highly efficient nucleotide pumps. The channel inhibitor hexacarboxybenzene is shown to block encapsidated reverse transcription, demonstrating the potential of the pore as an antiretroviral drug target. During the early stages of infection, the HIV-1 capsid protects viral components from cytosolic sensors and nucleases such as cGAS and TREX, respectively, while allowing access to nucleotides for efficient reverse transcription 1 . Here we show that each capsid hexamer has a size-selective pore bound by a ring of six arginine residues and a ‘molecular iris’ formed by the amino-terminal β-hairpin. The arginine ring creates a strongly positively charged channel that recruits the four nucleotides with on-rates that approach diffusion limits. Progressive removal of pore arginines results in a dose-dependent and concomitant decrease in nucleotide affinity, reverse transcription and infectivity. This positively charged channel is universally conserved in lentiviral capsids despite the fact that it is strongly destabilizing without nucleotides to counteract charge repulsion. We also describe a channel inhibitor, hexacarboxybenzene, which competes for nucleotide binding and efficiently blocks encapsidated reverse transcription, demonstrating the tractability of the pore as a novel drug target.

The capsid (CA) of the human immunodeficiency virus (HIV) has emerged as a critical therapeutic target owing to its essential roles in viral replication, nuclear import, and integration. Capsid inhibitors (CIs) disrupt these processes by binding to highly conserved structural interfaces, offering a novel mechanism distinct from enzyme-targeting antiretrovirals. In this review, we summarize the molecular architecture of the HIV-1 CA and its interactions with host factors, and we compare key structural and functional differences between HIV-1 and HIV-2. We provide an overview of established and investigational CIs, explore the resistance-associated mutations, their structural basis, and their impact on inhibitor potency, alongside insights into cross-resistance patterns. Special emphasis is placed on lenacapavir, exploring data from pivotal trials and emerging applications in both treatment and prevention, including long-acting pre-exposure prophylaxis (PrEP). Moreover, we highlight future perspectives, including the need for global surveillance of CA polymorphisms, strategies to overcome resistance, and challenges in accessibility and cost-effectiveness in resource-limited settings. Collectively, CIs represent a transformative addition to the HIV therapeutic arsenal, though their optimal deployment requires careful consideration of efficacy, resistance, and implementation barriers.

Due to the limited size of viral genomes, most viral proteins are multifunctional; yet most direct-acting antivirals are designed as single-function inhibitors. The dengue virus (DENV) capsid protein serves as a building block for new virions while also interacting with multiple host factors to remodel the cellular environment. Using established capsid inhibitor ST148 as a targeting ligand, we develop a DENV capsid degrader, RPG-01-132, that exhibits a broadened spectrum of activity against the four DENV serotypes and an ST148-resistant mutant virus. Using multiple approaches, we show that RPG-01-132’s sub-micromolar antiviral activity is due to CRL4 CRBN -dependent degradation of capsid and that this mechanism disrupts capsid-related pathways required for productive infection, including infectious virus output and capsid-mediated antagonism of the interferon response. This pharmacology is well-differentiated from ST148, which interferes with assembly of new virions, but has no demonstrated effect on the capsid’s nonstructural functions. These findings demonstrate that targeted protein degradation can thus enable antiviral pharmacology not observed with conventional antiviral inhibitors and that is resilient to point mutations that reduce inhibitor potency. The authors demonstrate that targeted protein degradation of the dengue virus capsid suppresses infection through capsid-dependent pathways rather than classical inhibition, revealing a new antiviral strategy effective against resistant viral variants.

Capsid assembly modulators (CAMs) represent a promising antiviral strategy against hepatitis B virus (HBV), but their effects on pre-formed capsids remain incompletely understood. Here, all-atom molecular dynamics (MD) simulations of intact HBV capsids complexed with prototypical CAM-As (HAP1, HAP18) and CAM-Es (AT130), reveal how structural changes induced by small molecule binding in the interdimer interfaces propagate through the shell lattice to yield global morphological consequences. Each quasi-equivalent interface exhibits a unique response: A sites, located within the pentameric capsomers, are unfilled in these systems and altered marginally by the presence of CAMs in neighboring interfaces. B sites are the most open and “CAM-ready,” suggesting uptake requires minimal conformational perturbation on the local or global level. C sites emerge as hubs of allosteric control and the key drug target, as their occupancy creates local distortion that is broadcast to adjacent sites, driving capsid faceting and – in the case of CAM-As – the destabilization that precedes dissociation in favor of aberrant assembly. D sites, unfilled in these systems, act as structural sinks, absorbing distortions from adjacent interfaces within the hexameric capsomers. The extent of C site adjustment and the nature of D site counterbalance varies with CAM chemotype, highlighting the divergent effects of CAM-As versus CAM-Es. The tensegrity relationship between the four quasi-equivalent interfaces couples them into a global network for strain redistribution that is functionally allosteric, with CAM binding sites displaying signs of both positive and negative cooperativity. These new insights into HBV capsid dynamics clarify how CAMs alter them on the microsecond timescale and suggest that targeting strain redistribution in mature core particles could be leveraged therapeutically.

Uncoating of the metastable HIV-1 capsid is a tightly regulated disassembly process required for release of the viral cDNA prior to nuclear import. To understand the intrinsic capsid disassembly pathway and how it can be modulated, we have developed a single-particle fluorescence microscopy method to follow the real-time uncoating kinetics of authentic HIV capsids in vitro immediately after permeabilizing the viral membrane. Opening of the first defect in the lattice is the rate-limiting step of uncoating, which is followed by rapid, catastrophic collapse. The capsid-binding inhibitor PF74 accelerates capsid opening but stabilizes the remaining lattice. In contrast, binding of a polyanion to a conserved arginine cluster in the lattice strongly delays initiation of uncoating but does not prevent subsequent lattice disassembly. Our observations suggest that different stages of uncoating can be controlled independently with the interplay between different capsid-binding regulators likely to determine the overall uncoating kinetics. Viruses need to enter their host’s cells in order to replicate their genetic material and produce more copies of the virus. A protein shell called a capsid protects the virus during this journey. But the structure of the capsid presents a mystery. How can this protein shell be strong enough to remain intact as it enters a host cell, and yet quickly open up to release the viral genome after replication? Unlike the capsids of many other viruses, those of HIV have irregular structures that rapidly fall apart once removed from the virus. This has thwarted attempts to study intact HIV capsids in order to understand how they work. However, we do know that HIV hijacks a range of molecules produced by the invaded host cell. Dissecting their effects on the capsid is key to understanding how the capsid disassembles. Márquez et al. have now developed a method that can visualize individual HIV capsids – and how they disassemble – in real time using single-molecule microscopy. This revealed that capsids differ widely in their stability. The shell remains closed for a variable period of time and then collapses catastrophically as soon as it loses its first subunit. Using the new technique, Márquez et al. also found that a small molecule drug called PF74 causes the capsid to crack open rapidly, but the remaining shell is then stabilized against further disassembly. These observations reconcile seemingly contradictory observations made by different research groups about how this drug affects the stability of the capsid. The method developed by Márquez et al. enables researchers to measure how molecules produced by host cells interact with the viral capsid, a structure that is fundamental for the virus to establish an infection. It could also be used to test the effects of antiviral drugs that have been designed to target the capsid. The new technique has already been instrumental in related research by Mallery et al., which identifies a molecule found in host cells that stabilizes the capsid of HIV.

The HIV-1 capsid has emerged as a highly attractive drug target due to its highly conserved sequence and critical role in the viral life cycle. By disrupting interactions between capsid proteins and impairing the proper assembly or disassembly of the capsid, the inhibitors can effectively suppress HIV-1 replication and infection. Based on this mechanism, numerous small-molecule agents targeting the HIV-1 capsid protein have been developed to date. In this review, we report the latest advances in such inhibitors and delve into their molecular mechanisms of action. We find a focus on small molecules modulating capsid stability and their assembly/disassembly. Hopefully this study will further enhance the understanding of HIV-1 inhibition mechanisms, facilitating the future exploration of novel capsid inhibitors.

Since the emergence of HIV and AIDS in the early 1980s, the development of safe and effective therapies has accompanied a massive increase in our understanding of the fundamental processes that drive HIV biology. As basic HIV research has informed the development of novel therapies, HIV inhibitors have been used as probes for investigating basic mechanisms of HIV-1 replication, transmission, and pathogenesis. This positive feedback cycle has led to the development of highly effective combination antiretroviral therapy (cART), which has helped stall the progression to AIDS, prolong lives, and reduce transmission of the virus. However, to combat the growing rates of virologic failure and toxicity associated with long-term therapy, it is important to diversify our repertoire of HIV-1 treatments by identifying compounds that block additional steps not targeted by current drugs. Most of the available therapeutics disrupt early events in the replication cycle, with the exception of the protease (PR) inhibitors, which act at the virus maturation step. HIV-1 maturation consists of a series of biochemical changes that facilitate the conversion of an immature, noninfectious particle to a mature infectious virion. These changes include proteolytic processing of the Gag polyprotein by the viral protease (PR), structural rearrangement of the capsid (CA) protein, and assembly of individual CA monomers into hexamers and pentamers that ultimately form the capsid. Here, we review the development and therapeutic potential of maturation inhibitors (MIs), an experimental class of anti-HIV-1 compounds with mechanisms of action distinct from those of the PR inhibitors. We emphasize the key insights into HIV-1 biology and structure that the study of MIs has provided. We will focus on three distinct groups of inhibitors that block HIV-1 maturation: (1) compounds that block the processing of the CA-spacer peptide 1 (SP1) cleavage intermediate, the original class of compounds to which the term MI was applied; (2) CA-binding inhibitors that disrupt capsid condensation; and (3) allosteric integrase inhibitors (ALLINIs) that block the packaging of the viral RNA genome into the condensing capsid during maturation. Although these three classes of compounds have distinct structures and mechanisms of action, they share the ability to block the formation of the condensed conical capsid, thereby blocking particle infectivity.