Bevirimat

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Bevirimat
File:Bevirimat.svg
Systematic (IUPAC) name
3β- (3-carboxy-3-methyl -butanoyloxy) lup-20(29)- en-28-oic acid
Clinical data
Routes of
administration		 Oral
Pharmacokinetic data
Metabolism Hepatic glucuronidation (UGT1A3-mediated)
Biological half-life 56.3 to 69.5 hours
Excretion fecal[1]
Identifiers
CAS Number 174022-42-5
ATC code none
PubChem CID 457928
Synonyms PA-457, 3-O-(3',3'-dimethylsuccinyl)- betulinic acid
Chemical data
Formula C36H56O6
Molar mass 584.826 g/mol[[Script error: No such module "String".]]
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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. [2] 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.[3]

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.[4] 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. [5]

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." [6]

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.[7] The resulting virus particles lack functional capsid protein and have structural defects, rendering them incapable of infecting other cells.[8] For reasons not entirely understood, protease inhibitor-resistant HIV-1 was hypersensitive to bevirimat in vitro.[9] In 2010 a study about bevirimat resistance prediction based on HIV-1 genotype has been published.[10]

References

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External links

External links

Antiviral drugs: antiretroviral drugs used against HIV (primarily J05)
Entry/fusion inhibitors
(Discovery & development)
Reverse transcriptase
inhibitors (RTIs)
(1st gen) Efavirenz°# · Nevirapine#  · Loviride◊ · Delavirdine◊ ·
(2nd gen) diarylpyrimidines (Etravirine, Rilpivirine†)  · Lersivirine†
Integrase inhibitors
Raltegravir · Elvitegravir† · Globoidnan A (experimental)  · MK-2048†  · GSK-572†
Maturation inhibitors
Bevirimat† · Vivecon†
Protease Inhibitors (PI)
(Discovery and development)
Combined formulations
Experimental agents
TRIM5alpha (gene)
Other
Failed agents
°DHHS preferred first-line agent. ◊Formerly or rarely used agent.
de:Bevirimat fr:Bevirimat
  1. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  2. ↑ Smith PF, Ogundele A, Forrest A, Wilton J, Salzwedel K, Doto J, Allaway GP, Martin DE. 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. Antimicrob Agents Chemother. 2007 Oct;51(10):3574-81. Epub 2007 Jul 16. PMID 17638699
  3. ↑ Myriad Genetics - Press Releases
  4. ↑ Zhou, Wanfeng. Panacos: Bevirimat data support further dose escalation. Thomson Financial News. 10 Dec 2007.
  5. ↑ Panacos - Press Releases
  6. ↑ 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. 
  7. ↑ 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. 
  8. ↑ bevirimat (PA-457). Panacos Pharmaceuticals Inc. accessed 28 Dec 2007.
  9. ↑ Stoddart CA, Joshi P, Sloan B; et al. (2007). "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 Freely accessible. PMID 18043758. 
  10. ↑ Heider D, Verheyen J, Hoffmann D. Predicting Bevirimat resistance in HIV-1 from genotype. BMC Bioinformatics, 11:37 [1]
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