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