Bevirimat

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Bevirimat
Systematic (IUPAC) name
3β- (3-carboxy-3-methyl -butanoyloxy) lup-20(29)- en-28-oic acid
Identifiers
CAS number	174022-42-5
ATC code	?
PubChem	457928
Chemical data
Formula	C₃₆H₅₆O₆
Mol. mass	584.826 g/mol
SMILES	eMolecules & PubChem
Synonyms	PA-457, 3-O-(3',3'-dimethylsuccinyl)- betulinic acid
Pharmacokinetic data
Bioavailability	?
Metabolism	Hepatic glucuronidation (UGT1A3-mediated)
Half life	56.3 to 69.5 hours
Excretion	?
Therapeutic considerations
Pregnancy cat.	?
Legal status
Routes	Oral

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. ^[1] It is not currently FDA-approved, but is undergoing clinical trials conducted by the pharmaceutical company Panacos.

1 Clinical trials
2 Pharmacokinetics
3 Mechanism of action
4 External links
5 References
6 External links

[edit] 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.^[2] The drug manufacturer, Panacos, has stated that success with Bevirimat hinges on a patients 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. ^[3]

[edit] 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." ^[4]

[edit] 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.^[5] The resulting virus particles lack functional capsid protein and have structural defects, rendering them incapable of infecting other cells.^[6] For reasons not entirely understood, protease inhibitor-resistant HIV-1 was hypersensitive to bevirimat in vitro.^[7]

[edit] External links

[edit] References

^ 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
^ 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.
^ 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.
^ bevirimat (PA-457). Panacos Pharmaceuticals Inc. accessed 28 Dec 2007.
^ 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. PMID 18043758.

[edit] External links

AIDSmeds Bevirimat

v • d • e Antivirals used against HIV (HAART) (primarily J05)

Nucleoside & Nucleotide Reverse Transcriptase Inhibitors (NRTI)	Abacavir (ABC)° • Emtricitabine° • Lamivudine (3TC)° • Tenofovir° • Didanosine • Zidovudine (AZT) • Apricitabine^† • Stampidine^† • Elvucitabine^† • Racivir^† • Amdoxovir^† • Stavudine^‡ • Zalcitabine^‡

Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI)	Efavirenz° • Nevirapine • Etravirine • Rilpivirine^† • Loviride^‡ • Delavirdine^‡

Protease Inhibitors (PI)	Atazanavir° • Fosamprenavir° • Lopinavir° • Darunavir • Nelfinavir • Ritonavir • Saquinavir • Tipranavir • Amprenavir^‡ • Indinavir^‡

Entry/fusion inhibitors	Enfuvirtide • Maraviroc • Vicriviroc^† • PRO 140^† • Ibalizumab^†

Integrase inhibitors	Raltegravir • Elvitegravir^†

Maturation inhibitors	Bevirimat^† • Vivecon™^†

Combined formulations	Combivir • Atripla • Trizivir • Truvada • Kaletra • Epzicom

Other & experimental agents	Foscarnet • Hydroxyurea • Synergistic enhancers • Epigallocatechin gallate • Portmanteau inhibitors • Globoidnan A • Griffithsin • Diarylpyrimidines • Calanolide A • Cyanovirin-N • Miltefosine • R-roscovitine^†

°DHHS preferred first-line agent. ^†Undergoing clinical trials, not FDA approved. ^‡Formerly or rarely used agent.