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Revision as of 15:14, 10 November 2011 by Beetstra (talk | contribs) (Script assisted update of identifiers for the Chem/Drugbox validation project (updated: 'CAS_number').)(diff) ← Previous revision | Latest revision (diff) | Newer revision → (diff) Pharmaceutical compound | |
| Clinical data | |
|---|---|
| Other names | PA-457, 3-O-(3',3'-dimethylsuccinyl)- betulinic acid |
| Routes of administration | Oral |
| ATC code |
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| Pharmacokinetic data | |
| Metabolism | Hepatic glucuronidation (UGT1A3-mediated) |
| Elimination half-life | 56.3 to 69.5 hours |
| Excretion | fecal |
| Identifiers | |
IUPAC name
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| PubChem CID | |
| ChemSpider | |
| UNII | |
| ChEMBL | |
| CompTox Dashboard (EPA) | |
| ECHA InfoCard | 100.125.475  |
| Chemical and physical data | |
| Formula | C36H56O6 |
| Molar mass | 584.826 g/mol g·mol |
| 3D model (JSmol) | |
SMILES
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InChI
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| (what is this?) (verify) | |
Bevirimat is an anti-HIV drug derived from a betulinic acid-like compound, first isolated from Syzygium claviflorum, a Chinese herb. It is believed to inhibit HIV by a novel mechanism, so-called maturation inhibition. It is not currently U.S. Food and Drug Administration (FDA) approved, but is undergoing clinical trials conducted by the pharmaceutical company Panacos. Myriad Genetics announced on January 21, 2009 the acquisition of all rights to Bevirimat for $7M USD.
Clinical trials
In December 2007, some results of the Phase IIb trial were released. Thomson Financial News reported that, "some patients respond 'very well' to the drug, while another population 'does not respond as well at current dose levels.'" Panacos said it intends to add a group to the study at a higher dosage. The drug manufacturer, Panacos, has stated that success with Bevirimat hinges on a patient's particular HIV not having a specific group of genetic mutations in HIV’s Gag protein. When they evaluated the study participants’ virus and found that the participant’s virologic response depended greatly on whether or not the Gag protein of a participant’s virus had polymorphisms—multiple mutations in the protein’s structure. After sampling the virus of 100 patients in the company’s database, they found that about 50 percent did not have Gag polymorphisms, meaning that about 50 percent would likely respond well to the drug.
Pharmacokinetics
According to the only currently available study, "the mean terminal elimination half-life of bevirimat ranged from 56.3 to 69.5 hours, and the mean clearance ranged from 173.9 to 185.8 mL/hour."
Mechanism of action
Like protease inhibitors, bevirimat and other maturation inhibitors interfere with protease processing of newly translated HIV polyprotein precursor, called gag. This molecule contains a number of HIV proteins in a single polypeptide which is then cleaved by the enzyme protease to produce functional structural proteins. However, unlike the protease inhibitors, bevirimat binds the gag protein, not protease. Once bound to gag, bevirimat prevents a critical cleavage at a site called the capsid-SP1 junction. The resulting virus particles lack functional capsid protein and have structural defects, rendering them incapable of infecting other cells. For reasons not entirely understood, protease inhibitor-resistant HIV-1 was hypersensitive to bevirimat in vitro. In 2010 a study about bevirimat resistance prediction based on HIV-1 genotype has been published.
References
- Bullock P, Larsen D, Press R, Wehrman T, Martin DE (2008). "The absorption, distribution, metabolism and elimination of bevirimat in rats". Biopharm Drug Dispos. 29 (7): 396–405. doi:10.1002/bdd.625. PMID 18615840.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) - Smith, PF; Ogundele, A; Forrest, A; Wilton, J; Salzwedel, K; Doto, J; Allaway, GP; Martin, DE (2007). "Phase I and II Study of the Safety, Virologic Effect, and Pharmacokinetics/Pharmacodynamics of Single-Dose 3-O-(3′,3′-Dimethylsuccinyl)Betulinic Acid (Bevirimat) against Human Immunodeficiency Virus Infection". Antimicrobial agents and chemotherapy. 51 (10): 3574–81. doi:10.1128/AAC.00152-07. PMC 2043264. PMID 17638699.
- Myriad Genetics - Press Releases
- Zhou, Wanfeng. Panacos: Bevirimat data support further dose escalation. Thomson Financial News. 10 Dec 2007.
- Panacos - Press Releases
- Martin DE, Blum R, Doto J, Galbraith H, Ballow C (2007). "Multiple-dose pharmacokinetics and safety of bevirimat, a novel inhibitor of HIV maturation, in healthy volunteers". Clin Pharmacokinet. 46 (7): 589–98. PMID 17596104.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - Salzwedel K, Martin DE, Sakalian M (2007). "Maturation inhibitors: a new therapeutic class targets the virus structure". AIDS Rev. 9 (3): 162–72. PMID 17982941.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - bevirimat (PA-457). Panacos Pharmaceuticals Inc. accessed 28 Dec 2007.
- Stoddart CA, Joshi P, Sloan B; et al. (2007). Kallas, Esper (ed.). "Potent Activity of the HIV-1 Maturation Inhibitor Bevirimat in SCID-hu Thy/Liv Mice". PLoS ONE. 2 (11): e1251. doi:10.1371/journal.pone.0001251. PMC 2080775. PMID 18043758.
{{cite journal}}: Explicit use of et al. in:|author=(help)CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link) - Heider D, Verheyen J, Hoffmann D. Predicting Bevirimat resistance in HIV-1 from genotype. BMC Bioinformatics, 11:37
External links
- AIDSmeds Bevirimat
- An animation illustrating Bevirimat's mechanism of action
- Overview and Publication Listing for Bevirimat from Panacos