Identification

Summary

Lenacapavir is a first-in-class capsid inhibitor being investigated for use in HIV-1 treatment.

Generic Name
Lenacapavir
DrugBank Accession Number
DB15673
Background

HIV/AIDS remains an area of concern despite the introduction of numerous successful therapies, mainly due to the emergence of multidrug resistance and patient difficulty in adhering to treatment regimens.1,2 Lenacapavir is a first-in-class capsid inhibitor that demonstrates picomolar HIV-1 inhibition as a monotherapy in vitro, little to no cross-resistance with existing antiretroviral agents, and extended pharmacokinetics with subcutaneous dosing.1,2,3,5

Lenacapavir was first globally approved by the European Commission to treat adults with multi-drug resistant HIV infection.7 It is currently being investigated in clinical trials in the US.

Type
Small Molecule
Groups
Investigational
Structure
Weight
Average: 968.28
Monoisotopic: 967.1435188
Chemical Formula
C39H32ClF10N7O5S2
Synonyms
  • Lenacapavir
External IDs
  • GS-CA1

Pharmacology

Indication

Lenacapavir, in combination with other antiretroviral(s), is indicated for the treatment of adults with multidrug resistant HIV-1 infection for whom it is otherwise not possible to construct a suppressive anti-viral regimen.6

Reduce drug development failure rates
Build, train, & validate machine-learning models
with evidence-based and structured datasets.
See how
Build, train, & validate predictive machine-learning models with structured datasets.
See how
Associated Conditions
Contraindications & Blackbox Warnings
Avoid life-threatening adverse drug events
Improve clinical decision support with information on contraindications & blackbox warnings, population restrictions, harmful risks, & more.
Learn more
Avoid life-threatening adverse drug events & improve clinical decision support.
Learn more
Pharmacodynamics

Lenacapavir is an antiviral drug with an extended pharmacokinetic profile. Lenacapavir works against the HIV-1 virus by inhibiting viral replication: it interferes with a number of essential steps of the viral lifecycle, including viral uptake, assembly, and release.6 Single subcutaneous doses ≥100 mg in healthy volunteers resulted in plasma concentrations exceeding the 95% effective concentration (EC95) for ≥12 weeks while doses ≥300 mg exceeded the EC95 for ≥24 weeks. In treatment-naive HIV-1-infected patients, a single subcutaneous dose of 20-450 mg resulted in a mean maximum log10-transformed reduction in plasma HIV-1 RNA of 1.35-2.20 by the ninth-day post-injection.2

Mechanism of action

HIV-1 co-opts various host factors during its replicative cycle, including during host cell entry, nuclear integration, replication, and virion assembly. Following the initial fusion with the host cell membrane, the viral capsid is released into the host cell cytoplasm. The capsid comprises approximately 250 hexamers and exactly 12 pentamers, each composed of monomeric capsid proteins (CA). Each CA monomer has an N-terminal and C-terminal domain (NTD/CTD) and offers an interaction surface for host cell machinery. Several important protein-protein interaction interfaces occur between CA monomers in the assembled multimers; the binding constants of these proteins are substantially lower for assembled multimers than individual capsid monomers.1

To facilitate HIV-1 genomic integration, the capsid must cross the nuclear envelope, for which it utilizes the nuclear pore complex (NPC). Two host proteins shown to be essential for capsid nuclear entry that directly bind to the capsid are cleavage and polyadenylation specificity factor subunit 6 (CPSF6) and nucleoporin 153 (Nup153, an NPC protein present on the nucleoplasmic face of the complex).1 Both proteins bind the same phenylalanine-glycine binding pocket between the NTD and CTD of neighbouring CA monomers in multimeric CA assemblies.1,2,3,4

Lenacapavir contains a difluorobenzyl ring that occupies the same binding pocket as CPSF6/Nup153, overlapping with the benzyl group of F321 in CPSF6 and F1417 in Nup153 in the overlayed structures.1,2,3,4 Crystal structures of lenacapavir bound to CA hexamers reveal that six lenacapavir molecules bind to each hexamer, establishing extensive hydrophobic interactions, two cation-π interactions, and seven hydrogen bonds, contacting ~2,000 Å2 of buried protein surface area.2,3 Strong binding of lenacapavir, therefore competitively interrupts capsid interactions with CPSF6 and Nup153. In vitro HIV-1 replication inhibition experiments in a variety of cell lines show EC50 values of ~12-314 pM, with greater efficacy against early steps over later steps.2,3 At very low concentrations (0.5 nM), lenacapavir inhibits viral nuclear entry, while at higher concentrations (5-50 nM), it additionally inhibits viral DNA synthesis and reverse transcription.3 As CPSF6 and Nup153 are essential for nuclear entry, it is likely that lenacapavir binding inhibits these interactions and blocks capsid nuclear entry.

Lenacapavir may have additional effects beyond blocking interactions with host cell factors. Lenacapavir increases the rate and extent of CA assembly, dramatically extends the lifetime of assembled CA structures, even at high salt concentrations, and alters assembled capsid morphology.2,3 The stabilizing concentration is ~1:1, closely mimicking the observed binding stoichiometry to isolated CA hexamers. Further analysis suggests that lenacapavir binding alters intra- and inter-hexamer interactions, altering the structure and stability of the resulting assemblies.3

Serial passage of HIV-1 in increasing concentrations of lenacapavir resulted in the appearance of major resistance mutations Q67H and N74D, which remain sensitive to other antiretroviral drugs. Extended passage resulted in the additional mutations L56I, M66I, K70N, N74S, and T107N. All identified resistance mutations map to the lenacapavir binding site, and all but the Q67H variant show reduced replication capacity in vitro.2 Additional studies have shown no lenacapavir resistance in variants associated with resistance to other antiretrovirals or naturally occurring polymorphisms, suggesting a very low potential for cross-resistance in combination therapy.5

TargetActionsOrganism
AGag-Pol polyprotein
inhibitor
Absorption

Following subcutaneous administration, lenacapavir is slowly released but completely absorbed, with peak plasma concentrations occurring at 84 days post-dose. Absolute bioavailability following oral administration is low, approximately 6 to 10%. Tmax after oral administration is about four hours. The mean steady-state Cmax (%CV) is 97.2 (70.3) ng/ mL following oral and subcutaneous administration.6

According to population pharmacokinetics analysis, lenacapavir exposures (AUCtau, Cmax and Ctrough) were 29% to 84% higher in heavily treatment-experienced patients with an HIV-1 infection compared to subjects without an HIV-1 infection. A low-fat meal had negligible effects on drug absorption.6

Volume of distribution

The steady state volume of distribution was 976 L in heavily treatment-experienced patients with an HIV-1 infection.6

Protein binding

In vitro, lenacapavir is approximately 99.8% bound to plasma proteins.6

Metabolism

Metabolism played a lesser role in lenacapavir elimination. It undergoes CYP3A4- and UGT1A1-mediated oxidation, N-dealkylation, hydrogenation, amide hydrolysis, glucuronidation, hexose conjugation, pentose conjugation, and glutathione conjugation. The metabolites of lenacapavir have not been fully characterized. No single circulating metabolite accounted for >10% of plasma drug-related exposure.6

Route of elimination

Following a single intravenous dose of radiolabelled-lenacapavir in healthy subjects, 76% of the total radioactivity was recovered from feces and less than 1% from urine. Unchanged lenacapavir was the predominant moiety in plasma (69%) and feces (33%).6

Half-life

The median half-life ranged from 10 to 12 days following following oral administration, and 8 to 12 weeks following subcutaneous administration.6

Clearance

Lenacapavir clearance was 3.62 L/h in heavily treatment experienced patients with HIV-1 infection.6

Adverse Effects
Improve decision support & research outcomes
With structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates.
Learn more
Improve decision support & research outcomes with our structured adverse effects data.
Learn more
Toxicity

There is limited information available regarding the acute toxicity and overdose of lenacapavir. If overdose occurs the patient must be monitored for signs or symptoms of adverse reactions. Treatment of overdose with lenacapavir consists of general supportive measures including monitoring of vital signs as well as observation of the clinical status of the patient. As lenacapavir is highly protein bound, it is unlikely to be significantly removed by dialysis.6

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbemaciclibThe metabolism of Abemaciclib can be decreased when combined with Lenacapavir.
AcalabrutinibThe metabolism of Acalabrutinib can be decreased when combined with Lenacapavir.
AcenocoumarolThe metabolism of Acenocoumarol can be decreased when combined with Lenacapavir.
Adenovirus type 7 vaccine liveThe therapeutic efficacy of Adenovirus type 7 vaccine live can be decreased when used in combination with Lenacapavir.
AlectinibThe metabolism of Alectinib can be decreased when combined with Lenacapavir.
AlpelisibThe metabolism of Alpelisib can be decreased when combined with Lenacapavir.
AminophyllineThe metabolism of Aminophylline can be decreased when combined with Lenacapavir.
AmiodaroneThe metabolism of Amiodarone can be decreased when combined with Lenacapavir.
Anthrax vaccineThe therapeutic efficacy of Anthrax vaccine can be decreased when used in combination with Lenacapavir.
ApalutamideThe metabolism of Lenacapavir can be increased when combined with Apalutamide.
Identify potential medication risks
Easily compare up to 40 drugs with our drug interaction checker.
Get severity rating, description, and management advice.
Learn more
Food Interactions
  • Take with or without food. Oral lenacapavir should be taken orally with or without food, as food has negligible effects on drug absorption.

Categories

ATC Codes
J05AX31 — Lenacapavir
Drug Categories
Classification
Not classified
Affected organisms
Not Available

Chemical Identifiers

UNII
A9A0O6FB4H
CAS number
2189684-44-2
InChI Key
BRYXUCLEHAUSDY-WEWMWRJBSA-N
InChI
InChI=1S/C39H32ClF10N7O5S2/c1-36(2,63(3,59)60)10-9-21-5-6-22(23-7-8-26(40)30-32(23)57(17-37(43,44)45)54-35(30)55-64(4,61)62)31(51-21)27(13-18-11-19(41)14-20(42)12-18)52-28(58)16-56-34-29(33(53-56)39(48,49)50)24-15-25(24)38(34,46)47/h5-8,11-12,14,24-25,27H,13,15-17H2,1-4H3,(H,52,58)(H,54,55)/t24-,25+,27-/m0/s1
IUPAC Name
N-[(1S)-1-{3-[4-chloro-3-methanesulfonamido-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl]-6-(3-methanesulfonyl-3-methylbut-1-yn-1-yl)pyridin-2-yl}-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-5,5-difluoro-9-(trifluoromethyl)-7,8-diazatricyclo[4.3.0.0^{2,4}]nona-1(6),8-dien-7-yl]acetamide
SMILES
[H][C@]12C[C@@]1([H])C(F)(F)C1=C2C(=NN1CC(=O)N[C@@H](CC1=CC(F)=CC(F)=C1)C1=NC(=CC=C1C1=CC=C(Cl)C2=C1N(CC(F)(F)F)N=C2NS(C)(=O)=O)C#CC(C)(C)S(C)(=O)=O)C(F)(F)F

References

General References
  1. Zhuang S, Torbett BE: Interactions of HIV-1 Capsid with Host Factors and Their Implications for Developing Novel Therapeutics. Viruses. 2021 Mar 5;13(3). pii: v13030417. doi: 10.3390/v13030417. [Article]
  2. Link JO, Rhee MS, Tse WC, Zheng J, Somoza JR, Rowe W, Begley R, Chiu A, Mulato A, Hansen D, Singer E, Tsai LK, Bam RA, Chou CH, Canales E, Brizgys G, Zhang JR, Li J, Graupe M, Morganelli P, Liu Q, Wu Q, Halcomb RL, Saito RD, Schroeder SD, Lazerwith SE, Bondy S, Jin D, Hung M, Novikov N, Liu X, Villasenor AG, Cannizzaro CE, Hu EY, Anderson RL, Appleby TC, Lu B, Mwangi J, Liclican A, Niedziela-Majka A, Papalia GA, Wong MH, Leavitt SA, Xu Y, Koditek D, Stepan GJ, Yu H, Pagratis N, Clancy S, Ahmadyar S, Cai TZ, Sellers S, Wolckenhauer SA, Ling J, Callebaut C, Margot N, Ram RR, Liu YP, Hyland R, Sinclair GI, Ruane PJ, Crofoot GE, McDonald CK, Brainard DM, Lad L, Swaminathan S, Sundquist WI, Sakowicz R, Chester AE, Lee WE, Daar ES, Yant SR, Cihlar T: Clinical targeting of HIV capsid protein with a long-acting small molecule. Nature. 2020 Aug;584(7822):614-618. doi: 10.1038/s41586-020-2443-1. Epub 2020 Jul 1. [Article]
  3. Bester SM, Wei G, Zhao H, Adu-Ampratwum D, Iqbal N, Courouble VV, Francis AC, Annamalai AS, Singh PK, Shkriabai N, Van Blerkom P, Morrison J, Poeschla EM, Engelman AN, Melikyan GB, Griffin PR, Fuchs JR, Asturias FJ, Kvaratskhelia M: Structural and mechanistic bases for a potent HIV-1 capsid inhibitor. Science. 2020 Oct 16;370(6514):360-364. doi: 10.1126/science.abb4808. [Article]
  4. Singh K, Gallazzi F, Hill KJ, Burke DH, Lange MJ, Quinn TP, Neogi U, Sonnerborg A: GS-CA Compounds: First-In-Class HIV-1 Capsid Inhibitors Covering Multiple Grounds. Front Microbiol. 2019 Jun 20;10:1227. doi: 10.3389/fmicb.2019.01227. eCollection 2019. [Article]
  5. Margot N, Ram R, Rhee M, Callebaut C: Absence of Lenacapavir (GS-6207) Phenotypic Resistance in HIV Gag Cleavage Site Mutants and in Isolates with Resistance to Existing Drug Classes. Antimicrob Agents Chemother. 2021 Feb 17;65(3). pii: AAC.02057-20. doi: 10.1128/AAC.02057-20. Print 2021 Feb 17. [Article]
  6. EMA Approved Drug Products: Sunlenca (lenacapavir) Subcutaneous Injection or Oral Tablets [Link]
  7. Gilead Press Releases: Gilead Announces First Global Regulatory Approval of Sunlenca® (Lenacapavir), the Only Twice-Yearly HIV Treatment Option [Link]
ChemSpider
81367881
ChEMBL
CHEMBL4594438
PDBe Ligand
QNG
Wikipedia
Lenacapavir
PDB Entries
6v2f / 6vkv / 7rhn / 7rj2 / 7rj4

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3RecruitingPreventionHIV Pre-Exposure Prophylaxis1
3RecruitingTreatmentHIV Pre-Exposure Prophylaxis1
2Active Not RecruitingTreatmentHuman Immunodeficiency Virus Type 1 (HIV-1) Infection1
2, 3Active Not RecruitingTreatmentHuman Immunodeficiency Virus Type 1 (HIV-1) Infection1
2, 3RecruitingTreatmentHuman Immunodeficiency Virus Type 1 (HIV-1) Infection1
1Active Not RecruitingTreatmentHuman Immunodeficiency Virus Type 1 (HIV-1) Infection1
1CompletedTreatmentHuman Immunodeficiency Virus Type 1 (HIV-1) Infection1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.00357 mg/mLALOGPS
logP6.47ALOGPS
logP6.4Chemaxon
logS-5.4ALOGPS
pKa (Strongest Acidic)6.69Chemaxon
pKa (Strongest Basic)1.91Chemaxon
Physiological Charge-1Chemaxon
Hydrogen Acceptor Count8Chemaxon
Hydrogen Donor Count2Chemaxon
Polar Surface Area157.94 Å2Chemaxon
Rotatable Bond Count14Chemaxon
Refractivity231.27 m3·mol-1Chemaxon
Polarizability83.29 Å3Chemaxon
Number of Rings7Chemaxon
Bioavailability0Chemaxon
Rule of FiveNoChemaxon
Ghose FilterNoChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleYesChemaxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Targets

Build, predict & validate machine-learning models
Use our structured and evidence-based datasets to unlock new
insights and accelerate drug research.
Learn more
Use our structured and evidence-based datasets to unlock new insights and accelerate drug research.
Learn more
Kind
Protein
Organism
Not Available
Pharmacological action
Yes
Actions
Inhibitor
Curator comments
Lenacapavir specifically binds to the interface between capsid (p24; CA) monomers in assembled capsid structures. The capsid protein is one of several cleavage products resulting from this polyprotein.
General Function
Zinc ion binding
Specific Function
Gag-Pol polyprotein: Mediates, with Gag polyrotein, the essential events in virion assembly, including binding the plasma membrane, making the protein-protein interactions necessary to create spher...
Gene Name
gag-pol
Uniprot ID
P04585
Uniprot Name
Gag-Pol polyprotein
Molecular Weight
162041.05 Da
References
  1. Zhuang S, Torbett BE: Interactions of HIV-1 Capsid with Host Factors and Their Implications for Developing Novel Therapeutics. Viruses. 2021 Mar 5;13(3). pii: v13030417. doi: 10.3390/v13030417. [Article]
  2. Link JO, Rhee MS, Tse WC, Zheng J, Somoza JR, Rowe W, Begley R, Chiu A, Mulato A, Hansen D, Singer E, Tsai LK, Bam RA, Chou CH, Canales E, Brizgys G, Zhang JR, Li J, Graupe M, Morganelli P, Liu Q, Wu Q, Halcomb RL, Saito RD, Schroeder SD, Lazerwith SE, Bondy S, Jin D, Hung M, Novikov N, Liu X, Villasenor AG, Cannizzaro CE, Hu EY, Anderson RL, Appleby TC, Lu B, Mwangi J, Liclican A, Niedziela-Majka A, Papalia GA, Wong MH, Leavitt SA, Xu Y, Koditek D, Stepan GJ, Yu H, Pagratis N, Clancy S, Ahmadyar S, Cai TZ, Sellers S, Wolckenhauer SA, Ling J, Callebaut C, Margot N, Ram RR, Liu YP, Hyland R, Sinclair GI, Ruane PJ, Crofoot GE, McDonald CK, Brainard DM, Lad L, Swaminathan S, Sundquist WI, Sakowicz R, Chester AE, Lee WE, Daar ES, Yant SR, Cihlar T: Clinical targeting of HIV capsid protein with a long-acting small molecule. Nature. 2020 Aug;584(7822):614-618. doi: 10.1038/s41586-020-2443-1. Epub 2020 Jul 1. [Article]
  3. Bester SM, Wei G, Zhao H, Adu-Ampratwum D, Iqbal N, Courouble VV, Francis AC, Annamalai AS, Singh PK, Shkriabai N, Van Blerkom P, Morrison J, Poeschla EM, Engelman AN, Melikyan GB, Griffin PR, Fuchs JR, Asturias FJ, Kvaratskhelia M: Structural and mechanistic bases for a potent HIV-1 capsid inhibitor. Science. 2020 Oct 16;370(6514):360-364. doi: 10.1126/science.abb4808. [Article]
  4. Singh K, Gallazzi F, Hill KJ, Burke DH, Lange MJ, Quinn TP, Neogi U, Sonnerborg A: GS-CA Compounds: First-In-Class HIV-1 Capsid Inhibitors Covering Multiple Grounds. Front Microbiol. 2019 Jun 20;10:1227. doi: 10.3389/fmicb.2019.01227. eCollection 2019. [Article]
  5. EMA Approved Drug Products: Sunlenca (lenacapavir) Subcutaneous Injection or Oral Tablets [Link]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
Inhibitor
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. EMA Approved Drug Products: Sunlenca (lenacapavir) Subcutaneous Injection or Oral Tablets [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Steroid binding
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform glucuronidates bilirubin IX-alpha to form both the...
Gene Name
UGT1A1
Uniprot ID
P22309
Uniprot Name
UDP-glucuronosyltransferase 1-1
Molecular Weight
59590.91 Da
References
  1. EMA Approved Drug Products: Sunlenca (lenacapavir) Subcutaneous Injection or Oral Tablets [Link]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da
References
  1. EMA Approved Drug Products: Sunlenca (lenacapavir) Subcutaneous Injection or Oral Tablets [Link]

Drug created at April 20, 2020 15:47 / Updated at December 01, 2022 11:30