Nelfinavir, sold under the brand name Viracept, is an antiretroviral medication used in the treatment of HIV/AIDS. Nelfinavir belongs to the class of drugs known as protease inhibitors (PIs) and like other PIs is almost always used in combination with other antiretroviral drugs.
Nelfinavir is an orally bioavailable human immunodeficiency virus HIV-1 protease inhibitor (Ki = 2 nM) and is widely prescribed in combination with HIV reverse transcriptase inhibitors for the treatment of HIV infection.[2]
It was patented in 1992 and approved for medical use in 1997.[3]
Nelfinavir can produce a range of adverse side effects. Flatulence, diarrhea, or abdominal pain are common (i.e. experienced by more than one in one hundred patients). Fatigue, urination, rash, mouth ulcers, or hepatitis are less frequent effects (experienced by one in one thousand to one in one hundred patients). Nephrolithiasis, arthralgia, leukopenia, pancreatitis, or allergic reactions may occur, but are rare (less than one in one thousand patients) .
Nelfinavir and simple derivatives have been found to inhibit the production of the virulence factorstreptolysin S, a cytolysin produced by the human pathogenStreptococcus pyogenes.[7] Nelfinavir and these related molecules did not exhibit detectable antibiotic activity, but did also inhibit the production of other biologically active molecules, including plantazolicin (antibiotic), listeriolysin S (cytolysin), and clostridiolysin S (cytolysin), by other bacteria.[7]
Nelfinavir's interaction profile is similar to that of other protease inhibitors. Most interactions occur at the level of the Cytochrome P450 isozymes 3A4 and CYP2C19, by which nelfinavir is metabolised.
Nelfinavir should be taken with food. Taking the drug with food decreases the risk of diarrhea as a side effect.
Mechanism of action
Nelfinavir is a protease inhibitor: it inhibits HIV-1 and HIV-2 proteases. HIV protease is an aspartate protease which splits viral protein molecules into smaller fragments, and it is vital to both the replication of the virus within the cell, and also to the release of mature viral particles from an infected cell. Nelfinavir is a competitive inhibitor[4] (2 nM) which is designed to bind tightly and is not cleaved due to the presence of a hydroxyl group as opposed to a keto group in the middle amino acid residue mimic, which would be otherwise S-phenylcysteine. All protease inhibitors bind to the protease, the precise mode of binding determines how the molecule inhibits the protease. The way Nelfinavir binds the enzyme may be sufficiently unique to reduce cross-resistance[clarification needed] between it and other PIs. Also, not all PIs inhibit both HIV-1 and HIV-2 proteases.
History
Nelfinavir was developed by Agouron Pharmaceuticals as part of a joint venture with Eli Lilly and Company.[8] Agouron Pharmaceuticals was acquired by Warner Lambert in 1999 and is now a subsidiary of Pfizer. It is marketed in Europe by Hoffman-La Roche and elsewhere by ViiV Healthcare.[citation needed]
The U.S. Food and Drug Administration (FDA) approved it for therapeutic use on March 14, 1997,[citation needed] making it the twelfth[citation needed] approved antiretroviral. The initial product launched proved to be the largest[citation needed] "biotech launch" in the history of the pharmaceutical industry, achieving first full year sales exceeding $US335M.[citation needed] Agouron's patent on the drug expired in 2014.
Since 2009, nelfinavir has been under investigation for potential use as an anti-cancer agent.[10] When applied to cancer cells in culture (in vitro), it can inhibit the growth of a variety of cancer types and can trigger cell death (apoptosis).[11] When Nelfinavir was given to laboratory mice with tumors of the prostate or of the brain, it could suppress tumor growth in these animals.[12][13] At the cellular level, nelfinavir exerts multiple effects to inhibit cancer growth; the two main ones appear to be inhibition of the Akt/PKB signaling pathway and activation of endoplasmic reticulum stress with subsequent unfolded protein response.[14]
In the United States, about three dozen clinical trials are being conducted (or have been completed) in order to determine whether nelfinavir is effective as a cancer therapeutic agent in humans.[15] In some of these trials, nelfinavir is used alone in monotherapy fashion, whereas in others it is combined with other modes of cancer therapy, such as well-established chemotherapeutic agents or radiation therapy.[citation needed]
^Chow WA, Jiang C, Guan M (January 2009). "Anti-HIV drugs for cancer therapeutics: back to the future?". The Lancet. Oncology. 10 (1): 61–71. doi:10.1016/S1470-2045(08)70334-6. PMID19111246.
^Yang Y, Ikezoe T, Takeuchi T, Adachi Y, Ohtsuki Y, Takeuchi S, et al. (July 2005). "HIV-1 protease inhibitor induces growth arrest and apoptosis of human prostate cancer LNCaP cells in vitro and in vivo in conjunction with blockade of androgen receptor STAT3 and AKT signaling". Cancer Science. 96 (7): 425–433. doi:10.1111/j.1349-7006.2005.00063.x. PMID16053514. S2CID44702882.
^Clinical trial number NCT03256916 for "A Phase III Randomized Clinical Trial to Study the Radiosensitizing Effect of Nelfinavir in Locally Advanced Carcinoma of Uterine Cervix." at ClinicalTrials.gov
(what is this?) (verify)
