CCR5 receptor antagonist
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CCR5 receptor antagonists are a class of
The life cycle of the HIV presents potential targets for drug therapy, one of them being the viral entry pathway. CCR5 and
History
Since the discovery of HIV in the 1980s, remarkable progress has been made in the development of novel
Mechanism of action
HIV enters host cells in the blood by attaching itself to
Drug development
As mentioned, the CCR5 receptor is a G-protein coupled receptor (GPCR). Before the discovery of CCR5's role in HIV infection, many pharmaceutical companies had already built a substantial collection of compounds that target GPCRs.[
Leronlimab
Leronlimab is a
Leronlimab is being developed by CytoDyn Inc. In May 2007, results from the phase I clinical trial of the drug demonstrated "potent, rapid, prolonged, dose-dependent, highly significant antiviral activity" for leronlimab. Participants in the highest-dosing group received 5 milligrams per kilogram and showed an average viral load decrease of -1.83 log10. On average, reductions of greater than -1 log10 per millilitre were maintained for between two and three weeks, from only a single dose of the drug.[23] The largest individual HIV RNA reductions ranged up to -2.5 log10 among patients receiving both the 2 and 5 mg/kg doses.[24]
Leronlimab is a lab-made antibody that functions as an
In February 2018, CytoDyn reported that the primary endpoint has been achieved in the PRO 140 pivotal combination therapy trial in HIV infection and will continue for an additional 24 weeks (end of August 2018) with PRO 140 weekly subcutaneous injections and optimized ART.[31] The report discloses that a single 350 mg subcutaneous injection of PRO 140 resulted in a HIV-1 RNA viral load reduction greater than 0.5log or 68% within one week compared with those who received a placebo. The primary efficacy endpoint results were presented at ASM Microbe 2018. In the pivotal trial of leronlimab in combination with standard anti-retroviral therapies in HIV-infected treatment-experienced patients, 81% of patients completing trial achieved HIV viral load suppression of < 50 cp/mL. Recent approved drugs for this population range from 43% after 24 weeks to 45% after 48 weeks with viral load suppression of < 50 cp/mL. In March 2019, CytoDyn filed with the US FDA the first part of the BLA for leronlimab (PRO140) as a combination therapy with HAART in HIV. In May 2020, the company filed its BLA with potential FDA approval in 4Q'20. CytoDyn is conducting an investigative monotherapy trial of leronlimab (PRO140) for HIV. If successful, once per week self-administered leronlimab would represent a paradigm shift in treatment of HIV.[32][33]
CytoDyn is investigating the use of leronlimab in various solid tumors. On February 18, 2019, CytoDyn announced it will begin 8 pre-clinical studies on melanoma cancer, pancreatic, breast, prostate, colon, lung, liver, and stomach cancer. This has the potential to lead to 8 phase II clinical studies with leronlimab in the cancer arena. On November 23, 2018, CytoDyn received FDA approval of its IND submission and allowed to initiate a Phase Ib/II clinical trial for metastatic triple-negative breast cancer (mTNBC) patients. On February 20, 2019, CytoDyn announced that leronlimab was able to reduce by more than 98% the incidence of human breast cancer metastasis in a mouse xenograft model for cancer through six weeks with leronlimab. The temporal equivalency of the murine 6 weeks study may be up to 6 years in humans. In May 2019, the U.S. Food and Drug Administration (FDA) granted fast track designation for leronlimab for use in combination with carboplatin for the treatment of patients with CCR5-positive mTNBC. In July 2019, CytoDyn announced the dosing of first mTNBC patient under compassionate use. Simultaneously, the Phase Ib/II trial for treatment-naïve mTNBC patients is active and anticipates top line data in 2020. If successful, the data from treatment-naïve mTNBC patients could serve as the basis for potentially seeking accelerated US FDA approval.[citation needed]
A study demonstrated leronlimab reduced the number and size of new human breast cancer metastasis in a mouse model and reduced the size of established metastasis thereby extending survival.[34]
In May 2019, CytoDyn initiated pre-clinical study of leronlimab to prevent NASH.[citation needed]
Aplaviroc
Aplaviroc is originated from a class of spirodiketopiperazine derivatives. Figure 2 shows the molecular structure of the lead compound and the final compound aplaviroc. The lead compound showed good potency in blocking CCR5 in a number of R5 HIV strains and against multi-drug resistant strains.[3] The problem with this compound was not its CCR5 selectivity but the oral bioavailability.[3][35] This led to further development of the molecule and the result was a compound named aplaviroc. Unfortunately, despite the promising preclinical and early clinical results, some severe liver toxicity was observed in the treatment of naïve and treatment-experienced patients that led to the discontinuation in further development of aplaviroc.[3]
Vicriviroc
Schering-Plough identified an
Maraviroc
Pfizer turned to high-throughput screening in their search for a good starting point for a small molecule CCR5 antagonist. Their screening resulted in a compound that presented weak affinity and no antiviral activity but represented a good starting point for further optimization.[3] Compounds 1–9 in Table 1 show the development of maraviroc in few steps. The chemical structure of the starting molecule (UK-107,543)[41] is presented as compound 1. Their first focus was to minimize CYP2D6 activity of the molecule and to reduce its lipophilicity. They replaced the imidazopyridine with benzimidazole and the benzhydril group was swapped out for a benzamide. The outcome was compound 2.[3] That compound showed good binding potency and the start of an antiviral activity. Further structure–activity relationship (SAR) optimization of the amide region and identifying the enantiomeric preference led to the cyclobutyl amide structure in compound 3. However, the problem with the CYP2D6 activity of the compound was still unacceptable so they had to perform further SAR optimization that determined that the [3.2.1]-azabicycloamine (tropane) could replace the aminopiperidine moiety. This change in the chemical structure led to compound 4. Compound 4 had no CYP2D6 activity while preserving excellent binding affinity and antiviral activity.[3][42] Although compound 4 showed promising results, it demonstrated 99% inhibition on the hERG ion channel. That inhibition was unacceptable since it can lead to QTc interval prolongation. The research team then did a few modifications to see which part of the molecule played a role in the hERG affinity. Compound 5 shows an analogue that they synthesized which contained an oxygen bridgehead in the tropane ring; however, that reconstruction did not have an effect on the hERG affinity.[43] They then focused on the polar surface area in the molecule to dial out the hERG affinity. These efforts resulted in compound 6. That compound preserved desired antiviral activity and was selective against the hERG inhibition but the problem was its bioavailability. Reduction in the lipophilicity, by replacing the benzimidazol group with a substituted triazole group gave compound 7. Compound 7 had shown a significant reduction in lipophilicity and maintained the antiviral activity but again, with the introduction of a cyclobutyl group, the compound showed hERG inhibition. Changing the ring size in compound 7 from a cyclobutyl unit to a cyclopentyl unit in compound 8 led to a significant increase in antiviral activity and loss of hERG affinity. Further development led to discovery of a 4,4'-difluorocyclohexylamide also known as maraviroc. Maraviroc preserved excellent antiviral activity, whilst demonstrating no significant hERG binding affinity. The lack of hERG binding affinity was predicted to be because of the large size of the cyclohexyl group and the high polarity of the fluoro substituents.[3][42][43] In August 2007 the FDA approved the first CCR5 antagonist, maraviroc, discovered and developed by Pfizer.[4][7]
Pharmacophore
The predictive pharmacophore model was developed for a large series of piperidine- and piperazine-based CCR5 antagonists by Schering-Plough Research Institute. Their hypothesis consisted of mostly five features, two hydrogen bond acceptors, marked C and D in figure 4 and three hydrophobic groups, A, B and E in figure 4. Part B usually has a basic nitrogen group. The model was validated using diverse set of six CCR5 antagonists from five different pharmaceutical companies. The best model correctly predicted these compounds as being highly active. It is possible to use the model as a tool in virtual screening for new small molecular CCR5 antagonists and also to predict biological activities of compounds prior to undertaking their costly synthesis.[44]
Binding
CCR5 is a member of G protein-coupled, seven transmembrane segment receptors. The structure of the receptor comprises seven-helix bundle in the transmembrane region, these regions are labeled I–VII in figures 5 and 6. The CCR5 antagonists are predicted to bind to a putative binding pocket which is buried inside the transmembrane domain, enclosed by the seven transmembrane helices. The binding pocket is very hydrophobic with multiple aromatic residues lining the pocket. The key residues are
Aplaviroc
The putative binding mode for aplaviroc is shown in figure 5. The key saltbridge interaction between aplaviroc and Glu283 is predicted to be quite weak compared to other CCR5 antagonists. The hydroxyl group on aplaviroc forms a strong hydrogen bond to the polar residue Thr195. This H-bond interaction is the strongest with aplaviroc compared to other CCR5 antagonists. The cyclohexyl group in the aplaviroc structure is predicted to interact with the receptor in a hydrophobic pocket formed by Ile198, Thr195 and Phe109 and is thought to show quite strong hydrophobic interactions. The researchers predict that the butyl group of aplaviroc is buried within the helical bundle through strong hydrophobic interaction with multiple aromatic residues of the CCR5 receptor.[46] Aplaviroc has a unique feature of preserving two of the natural chemokine protein ligands binding to CCR5 and subsequent activation, whereas maraviroc and the other antagonists almost fully block chemokine-CCR5 interactions. This kind of interference is so far considered to be safe, and individuals that naturally lack CCR5 do not show any obvious health problems. However, to limit the toxicity and side effects of CCR5 antagonists it would be ideal to be able to preserve the chemokine receptor function. Consequently, it should be of interest to design inhibitors that specifically disrupt CCR5–gp120 binding but do not affect the CCR5 chemokine activation.[47]
Maraviroc
The putative binding mode for maraviroc is shown in figure 6. The strongest interaction is estimated to be between maraviroc and glutamic acid (Glu283) through a strong salt bridge interaction. The interaction between tryptophan (Trp86) and maraviroc involves T-shaped π-π stacking while the interaction with phenylalanine (Phe109) is predicted to be hydrophobic. Tyrosine (Tyr108) is thought to interact with the phenyl group on maraviroc through a parallel displaced interaction. The interaction between maraviroc and isoleucine (Ile198) is predicted to be mostly hydrophobic in nature and the interaction between maraviroc and tyrosine (Tyr251) is very limited.[46]
Other CCR5 antagonists
Development of new CCR5 antagonists continues, both for their antiviral effects and also for potential utility in a variety of autoimmune indications. Researchers at Roche Palo Alto discovered a novel series of potent CCR5 small-molecule antagonists. Lead optimization was pursued by balancing opposing trends of metabolic stability and potency. Combination of the spiropiperidine template with pharmacophore elements from both aplaviroc, and Schering's CCR5 antagonist program, led to the initial lead compound in this series. Further development of that lead compound led to the discovery of compound A in figure 7 — a compound that possesses a good selectivity and pharmacokinetic properties.[49]
The CCR5 antagonist INCB009471 has
Not only small molecules but also proteins delivered by gene therapy have been suggested to ablate CCR5 function,[51] an approach that has also been employed for other HIV targets.[52]
See also
- HIV/AIDS research
- Cenicriviroc
- CD4
- CCL5
- CCR5
- Subtypes of HIV
- HIV tropism
- Discovery and development of non-nucleoside reverse transcriptase inhibitors
- Discovery and development of nucleoside and nucleotide reverse-transcriptase inhibitors
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