Clinical targeting of HIV capsid protein with a long-acting small molecule

  title={Clinical targeting of HIV capsid protein with a long-acting small molecule},
  author={John O. Link and Martin S. Rhee and Winston C. Tse and Jim Zheng and John R. Somoza and William Rowe and Rebecca Begley and Anna Chiu and Andrew S Mulato and Derek Hansen and Eric Singer and Luong K. Tsai and Rujuta A. Bam and Chien-Hung Chou and Eda Canales and Gediminas J. Brizgys and Jennifer R. Zhang and Jiayao Li and Michael Graupe and Philip Anthony Morganelli and Qi Liu and Qiaoyin Wu and Randall L. Halcomb and R. Saito and Scott D. Schroeder and Scott E. Lazerwith and Steven S. Bondy and Debi Jin and Magdeleine Hung and Nikolai Novikov and Xiaohong Liu and Armando G. Villaseñor and Carina E. Cannizzaro and Eric Hu and Robert L. Anderson and Todd C. Appleby and Bing Lu and Judy Mwangi and Albert C Liclican and Anita Niedziela-Majka and Giuseppe A. Papalia and Melanie H. Wong and Stephanie A. Leavitt and Yili Xu and David Koditek and George J Stepan and Helen Yu and Nikos C. Pagratis and Sheila Clancy and Shekeba Ahmadyar and Terrence Cai and Scott Sellers and Scott Alan Wolckenhauer and John Ling and C. Callebaut and Nicolas A Margot and Renee R Ram and Yapei Liu and Robert H. Hyland and Gary I. Sinclair and Peter Ruane and Gordon E. Crofoot and Cheryl Mcdonald and Diana M. Brainard and Latesh Lad and Swami Swaminathan and Wesley I. Sundquist and Roman Sakowicz and Anne E. Chester and William E. Lee and Eric S Daar and Stephen R Yant and Tomas Cihlar},
Oral antiretroviral agents provide life-saving treatments for millions of people living with HIV, and can prevent new infections via pre-exposure prophylaxis 1 – 5 . However, some people living with HIV who are heavily treatment-experienced have limited or no treatment options, owing to multidrug resistance 6 . In addition, suboptimal adherence to oral daily regimens can negatively affect the outcome of treatment—which contributes to virologic failure, resistance generation and viral… 

Long-Acting Injectable Antiretroviral Agents for HIV Treatment and Prevention

  • Y. Kim
  • Biology, Medicine
    Infection & chemotherapy
  • 2021
This review summarizes the data of efficacies and safety profiles of LA CAB with RPV regimen, and also new long-acting injectable antiretroviral agents in pipeline.

Long-acting antiretrovirals: a new era for the management and prevention of HIV infection

The present review aims to update the current state of knowledge on these novel promising LA-ARTs and discusses their implications, particularly from a clinical pharmacokinetics perspective, for the future management and prevention of HIV infection, issues of ongoing importance in the absence of curative treatment or an effective vaccine.

Structural and mechanistic bases for a potent HIV-1 capsid inhibitor

It is found that GS-6207 inhibits HIV-1 by stabilizing and thereby preventing functional disassembly of the capsid shell in infected cells, providing a platform for the rational development of improved long-acting therapies.

Structural and Mechanistic Bases of Viral Resistance to HIV-1 Capsid Inhibitor Lenacapavir

High resolution structures of the main drug resistant capsid variants are determined, which provide mechanistic insight into the viral resistance to LEN, and an improved inhibitor is developed, which exhibited enhanced activity against the viral Q67H/N74D capsid phenotype compared with that of parental LEN.

HIV-1 Maturation: Lessons Learned from Inhibitors

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, are reviewed.

Capsid Inhibition with Lenacapavir in Multidrug-Resistant HIV-1 Infection.

In patients with multidrug-resistant HIV-1 infection, patients who received lenacapavir had a greater reduction from baseline in viral load than those who received placebo.

Novel and Investigational HIV Therapies for Treatment and Prevention: Focus on Cabotegravir, Islatravir, and Lenacapavir

Clinical data have supported long-acting cabotegravir’s approval for treatment and pre-exposure prophylaxis of HIV while islatravir and lenacapavir remain in investigation status.

Long-acting injectable HIV therapies: the next frontier: Republication

Despite evidence that suggests that these therapies are efficacious and acceptable to patients, the challenge of integrating these agents into the current healthcare infrastructure and making these novel agents cost-effective and available to the populations most likely to benefit remains.



A highly potent long-acting small-molecule HIV-1 capsid inhibitor with efficacy in a humanized mouse model

GS-CA1 is reported, 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.

Long-Acting HIV Drugs for Treatment and Prevention.

Although long-acting antiretroviral drugs hold promise, some clinical challenges exist, including managing side effects, drug-drug interactions, pregnancy, and long-lasting drug concentrations that could lead to the development of drug resistance.

Inhibitors of the HIV-1 capsid, a target of opportunity

Capsid-targeting drugs are predicted to exhibit high barriers to viral resistance, and ongoing work in this area is contributing to an understanding of the molecular biology of HIV uncoating and maturation.

Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys

These results show the first substantive post-exposure protection by a small-molecule antiviral compound against EBOV in nonhuman primates, and the broad-spectrum antiviral activity of GS-5734 in vitro against other pathogenic RNA viruses, including filoviruses, arenavirus, and coronavirus suggests the potential for wider medical use.

Functional conservation of HIV-1 Gag: implications for rational drug design

This first large-scale analysis of full-length HIV-1 gag provided a detailed mapping of natural diversity across major subtypes and highlighted the considerable variation in current drug binding sites.

Prevalence of gag mutations associated with in vitro resistance to capsid inhibitor GS-CA1 in HIV-1 antiretroviral-naive patients

Sir,We report on the case of an HIV/HCV-coinfected patient in her mid-40s with porphyria cutanea tarda (PCT) treated with sofosbu-vir/ledipasvir who achieved a sustained virological response (SVR)

Phenotypic Susceptibility to Bevirimat in Isolates from HIV-1-Infected Patients without Prior Exposure to Bevirimat

In vitro phenotypic analyses of viruses made from patient samples confirmed the role of the V370A SP1 polymorphism (SP1-V7A) in resistance to Bevirimat and demonstrated for the first time that a capsid polymorphism, V362I (CA protein-V230I), is also a major mutation conferring resistance to BVM.

Antiviral Activity of Bictegravir (GS-9883), a Novel Potent HIV-1 Integrase Strand Transfer Inhibitor with an Improved Resistance Profile

The overall virologic profile of BIC supports its ongoing clinical investigation in combination with other antiretroviral agents for both treatment-naive and -experienced HIV-infected patients.

Phase 3 Study of Ibalizumab for Multidrug‐Resistant HIV‐1

In patients with MDR HIV‐1 infection who had advanced disease and limited treatment options, ibalizumab had significant antiviral activity during a 25‐week study and in vitro testing identified 9 patients who had a lower degree of susceptibility to ibalIZumab than at baseline.

TLR7 Agonist GS-9620 Is a Potent Inhibitor of Acute HIV-1 Infection in Human Peripheral Blood Mononuclear Cells

Investigation of the in vitro anti-HIV-1 activity of GS-9620 found that it inhibited a postentry event in HIV replication at a step coincident with or prior to reverse transcription, suggesting these antiviral effects may help restrict potential local HIV spread upon in vivo latency reversal.