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Newer category of Anti-Hiv drugs in clinical trial
By- ARUP SAHA M.Pharm,1st sem
Some HIV Facts
• HIV – the Human Immunodeficiency Virus is the retrovirus that causes AIDS
• HIV belongs to the retrovirus subfamily lentivirus.
• HIV attaches to cells with CD4 receptors (T4 cells and macrophages).
HIV Life Cycle1
Step 1: Attachment of virus at the CD4 receptor and chemokine co-receptors CXCR4 or CCR5
Step 2: viral fusion and uncoatingStep 3: Reverse transcriptase makes a
single DNA copy of the viral RNA and then makes another to form a double stranded viral DNA
Step 4: Now the viral DNA transported across the nucleus and Integration of the viral DNA into cellular DNA by the enzyme integrase
Step 5: Transcription and RNA processingStep 6: Protein synthesis occurred and
new viral RNA and protein move to the cell surface and a new immune HIV forms
Step 7: Now the virion matured
Current classes of antiretroviral drugs include :
Fusion or Entry Inhibitors
Nucleoside/Nucleotide Reverse Transcriptase Inhibitors
Non-Nucleoside Reverse Transcriptase Inhibitors
Protease Inhibitors Integrase Inhibitors
Fusion or Entry Inhibitors
• It inhibit HIV from entering to the human cells. • There are two types:Fusion inhibitors CCR5 inhibitors CCR5 inhibitors won’t work in everyone and are
not often used for first-line treatment.
Fusion or Entry Inhibitors There is currently one drug
in the fusion inhibitor class, called T-20
(enfuvirtide, Fuzeon).Enfuvirtide is the
first fusion inhibitor drug. This is now only prescribed in very
rare and specific circumstances.
Drug used for CCR5 inhibitors are Maraviroc, Celsentri.
Nucleoside/Nucleotide Reverse Transcriptase Inhibitors
• Nucleoside reverse transcriptase inhibitors (NRTIs) and nucleotide reverse transcriptase
inhibitors (NtRTIs), which target an HIV protein
called reverse transcriptase,• This class of drugs forms the
‘backbone’ of a firstline HIV treatment combination and is usually
taken in a pill that combines a number of drugs
Currently Available Nucleoside Analogs (NRTI’s)
• zidovudine/Retrovir
• didanosine/Videx• zalcitabine/HIVID • stavudine/Zerit • lamivudine/Epivir
• abacavir/Ziagen
Zidovudine/Retrovir
didanosine/Videx
Non-Nucleoside Reverse Transcriptase Inhibitors
• Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs), started to be approved in 1997.
• Like the Nucleoside Inhibitors, NNRTIs (also known as non-nucleosides) stop HIV from replicating within cells by inhibiting the reverse transcriptase protein.
• Three NNRTI’s are currently approved for clinical use in combination therapy: nevirapine, delavirdine, and efavirenz
Efavirenz
Delavirdine
Protease inhibitors (PIs)• During the reproduction cycle of HIV a specific
protease is needed to process polyproteins into mature HIV components.
• If protease is missing noninfectious HIV is produced.• HIV protease inhibitors are specific to HIV protease
because it differs significantly from human protease. • The 6 PI’s currently approved for clinical use were all
designed by using structure-based drug design methods4.
Protease inhibitor• indinavir/Crixivan• ritonavir/Norvirs• aquinavir/Invirase,
Fortovase• nelfinavir/Viracept• amprenavir/Ageneras• elopinavir/ritonavir,
Kaletra
Indinavir/Crixivan
Nelfinavir/Viracept
Integrase Inhibitors
• Integrase inhibitors, which target a protein in HIV called integrase, and stop the virus from
integrating into the DNA of human cells.
Drugs which are used as anti integrase inhibitors are Raltegravir, Isentress
Raltegravir
Cabotegravir : It is an investigational new drug under development for the treatment of HIV infection.It is an integrease inhibitor. This would make possible suppression of HIV with dosing as infrequently as once every three months
Cenicriviroc :Cenicriviroc is an inhibitor of CCR2 and CCR5 receptors allowing it to function as an entry inhibitor which prevents the virus from entering into a human cell. Inhibition of CCR2 may have an anti-inflammatory effect
Anti HIV drug in clinical trial
Doravirine : Doravirine is a non-nucleoside reverse transcriptase inhibitor for use in the treatment of HIV/AIDS under development by Merck & Co. This is now in clinical phase III
Elvucitabine : It belongs to a class of HIV drugs called nucleoside reverse transcriptase inhibitors (NRTIs).Scientists are said that elvucitabine may be effective against hepatitis B virus (HBV)Currently, it is in Phase II clinical trials.
Fosdevirine : It is a Non-nucleoside Reverse Transcriptase Inhibitors and developed by Idenix Pharmaceuticals.Currently it is in Phase of Development II .
CENSAVUDINE : It is an investigational new drug being developed by Bristol Myers-Squibb for the treatment of HIV infection. Censavudine is a nucleoside reverse transcriptase inhibitor.
Doravirine : It is a non-nucleoside reverse transcriptase inhibitor under development by Merck & Co. for use in the treatment of HIV/AIDS.Doravirine appeared safe and generally well-tolerated with most adverse events being mild-to-moderate.
Apricitabine : sometimes abbreviated to ATC is an experimental nucleoside reverse transcriptase inhibitor (NRTI) against HIV. It is clinical phase III.
PRO 140 : It could be the first self-injectable HIV antibody on the global market. PRO 140 belongs to a new class of HIV/AIDS therapeutics -- viral-entry inhibitors -- that are intended to protect healthy cells from viral infection. it is developed by CYTODYN. If all goes well CytoDyn could submit its NDA (New Drug Application) for final approval in November 2016 and it will marketed in 2017.
First self-injectable HIV antibody
REFERANCE
• An Introduction to Medicinal Chemistry by Graham L. Patrick
• https://aidsinfo.nih.gov/clinical-trials• https://Wikipedia .com