Chemistry:Nelfinavir

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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, it 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.[1]

It was patented in 1992 and approved for medical use in 1997.[2]

Toxicity

Common (>1%) adverse effects include insulin resistance, hyperglycemia, and lipodystrophy.[3]

Nelfinavir can produce a range of adverse effects. Flatulence, diarrhea, or abdominal pain are common (i.e. experienced by more than one in a hundred patients). Fatigue, urination, rash, mouth ulcers, or hepatitis are less frequent effects (experienced by one in a thousand to one in a hundred patients). Nephrolithiasis, arthralgia, leukopenia, pancreatitis, or allergic reactions may occur, but are rare (less than one in a thousand patients) .

Other bioactivity

Antiviral

Nelfinavir inhibits the maturation and export of the herpes simplex 1 virus[4] and the Kaposi's sarcoma virus.[5]

Anti-virulence activity

Nelfinavir and simple derivatives inhibit the production of the virulence factor streptolysin S, a cytolysin produced by the human pathogen Streptococcus pyogenes.[6] Nelfinavir and its derivatives did not exhibit detectable antibiotic activity, but did inhibit the production of other biologically active molecules, including plantazolicin (antibiotic), listeriolysin S (cytolysin), and clostridiolysin S (cytolysin), by other bacteria.[6]

Interactions

Nelfinavir's interaction profile is similar to that of other protease inhibitors. Most interactions occur at the level of the cytochrome P450 isozymes CYP3A4 and CYP2C19, by which nelfinavir is metabolized. For example, nelfinavir reportedly inhibited the metabolism of atorvastatin and simvastatin.[7]

Pharmacology

Nelfinavir should be taken with food. Taking the drug with food reduces the risk of diarrhea as an adverse effect.[8]

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 is vital to both replication of the virus within the cell and also to release of mature viral particles from an infected cell. Nelfinavir is a competitive inhibitor[3] (2 nM), which is designed to bind tightly and is not cleaved because of 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, and the precise mode of binding determines how the molecule inhibits the protease. The way in which 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.[9] Agouron Pharmaceuticals was acquired by Warner Lambert in 1999 and is now a subsidiary of Pfizer. Nelfinavir is marketed in Europe by Hoffman-La Roche and elsewhere by ViiV Healthcare.[citation needed]

The US Food and Drug Administration (FDA) approved nelfinavir for therapeutic use in March 1997, making it the twelfth{{Citation needed|date=April 2011} ial product launched proved to be the largest[citation needed] "biotech launch" in the history ing first full year sales exceeding $US335M.[citation needed] Agouron's patent on the drug expired in 2014. In June 2007, both the Medicines and Healthcare products Regulatory Agency and the European Medicines Agency[10] put out an alert requesting the recall of any nelfinavir in circulation, because some batches may have been contaminated with potentially cancer-causing chemicals.

Research

Since 2009, nelfinavir has been under investigation for potential use as an anti-cancer agent.[11] 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).[12] When nelfinavir was given to laboratory mice with tumours of the prostate or of the brain, it suppressed tumour growth.[13][14] 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.[15]

In the USA, 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.[16] In some of these trials, nelfinavir has been used alone in monotherapy, whereas in others it has been combined with other modes of cancer therapy, such as well-established chemotherapeutic agents[17] or radiation therapy.[18]

As of April 2022, nelfinavir is being studied as a radiosensitizing agent as part of treatment of advanced cervical cancer.[19]

References

  1. ↑ "Circulating metabolites of the human immunodeficiency virus protease inhibitor nelfinavir in humans: structural identification, levels in plasma, and antiviral activities". Antimicrobial Agents and Chemotherapy 45 (4): 1086–1093. April 2001. doi:10.1128/AAC.45.4.1086-1093.2001. PMID 11257019. 
  2. ↑ (in en) Analogue-based Drug Discovery. John Wiley & Sons. 2006. pp. 510. ISBN 978-3-527-60749-5. https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA510. 
  3. ↑ 3.0 3.1 "Recent advances in drug repositioning for the discovery of new anticancer drugs". International Journal of Biological Sciences 10 (7): 654–663. 2014. doi:10.7150/ijbs.9224. PMID 25013375. 
  4. ↑ "Nelfinavir inhibits maturation and export of herpes simplex virus 1". Journal of Virology 88 (10): 5455–5461. May 2014. doi:10.1128/JVI.03790-13. PMID 24574416. 
  5. ↑ "The HIV protease inhibitor nelfinavir inhibits Kaposi's sarcoma-associated herpesvirus replication in vitro". Antimicrobial Agents and Chemotherapy 55 (6): 2696–2703. June 2011. doi:10.1128/AAC.01295-10. PMID 21402841. 
  6. ↑ 6.0 6.1 "HIV protease inhibitors block streptolysin S production". ACS Chemical Biology 10 (5): 1217–1226. May 2015. doi:10.1021/cb500843r. PMID 25668590. 
  7. ↑ "Pharmacokinetic interactions between nelfinavir and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors atorvastatin and simvastatin". Antimicrob Agents Chemother 45 (12): 3445–3450. 2001. doi:10.1128/AAC.45.12.3445-3450.2001. PMID 11709322. 
  8. ↑ "Chapter 21 - Acquired Immunodeficiency Syndrome in the Infant". Infectious Diseases of the Fetus and Newborn Infant (Sixth ed.). Philadelphia: W.B. Saunders. 2006-01-01. pp. 667–692. doi:10.1016/b0-72-160537-0/50023-2. ISBN 978-0-7216-0537-1. 
  9. ↑ "Viracept (nelfinavir mesylate, AG1343): a potent, orally bioavailable inhibitor of HIV-1 protease". Journal of Medicinal Chemistry 40 (24): 3979–3985. November 1997. doi:10.1021/jm9704098. PMID 9397180. 
  10. ↑ Press release from the European Medicines Agency regarding possible genotoxic ethyl mesylate contamination
  11. ↑ "Anti-HIV drugs for cancer therapeutics: back to the future?". The Lancet. Oncology 10 (1): 61–71. January 2009. doi:10.1016/S1470-2045(08)70334-6. PMID 19111246. 
  12. ↑ "Nelfinavir, A lead HIV protease inhibitor, is a broad-spectrum, anticancer agent that induces endoplasmic reticulum stress, autophagy, and apoptosis in vitro and in vivo". Clinical Cancer Research 13 (17): 5183–5194. September 2007. doi:10.1158/1078-0432.CCR-07-0161. PMID 17785575. 
  13. ↑ "HIV-1 protease inhibitors nelfinavir and atazanavir induce malignant glioma death by triggering endoplasmic reticulum stress". Cancer Research 67 (22): 10920–10928. November 2007. doi:10.1158/0008-5472.CAN-07-0796. PMID 18006837. 
  14. ↑ "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. July 2005. doi:10.1111/j.1349-7006.2005.00063.x. PMID 16053514. 
  15. ↑ "Nelfinavir and other protease inhibitors in cancer: mechanisms involved in anticancer activity". F1000Research 4 (2): 9. 2015. doi:10.12688/f1000research.5827.2. PMID 26097685. 
  16. ↑ "Search of: Nelfinavir cancer - List Results - ClinicalTrials.gov". https://clinicaltrials.gov/ct2/results?term=Nelfinavir+cancer. 
  17. ↑ "ER-phagy mediates the anti-tumoral synergism between HDAC inhibition and chemotherapy". Cell Communication and Signaling 23 (1). April 2025. doi:10.1186/s12964-025-02198-9. PMID 40287668. 
  18. ↑ "Phase I/II Trial of Neoadjuvant Oregovomab-based Chemoimmunotherapy Followed by Stereotactic Body Radiotherapy and Nelfinavir For Locally Advanced Pancreatic Adenocarcinoma". American Journal of Clinical Oncology 42 (10): 755–760. October 2019. doi:10.1097/COC.0000000000000599. PMID 31513018. 
  19. ↑ 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

Further reading



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