Drug Discovery Process

Study Sheet – Dr. Kerwin’s Portion

Drug Discovery Process

-  Know the major Milestones in drug discovery/development:

• Investigational New Drug Application (IND) required before first human dose/clinical trials

• New Drug Application (NDA) required before FDA can approve new drug

-  Know the average time, cost, and number of compounds tested that are required to bring one drug to market

• 15 years, $450-500M, 10,000 compounds

-  Know the different clinical trial phases

• Phase 1, health volunteers receive drug in order to test for safety and set the dose level for future phases

• Phase 2, a small group (dozens to ~100) receive standard dose to further assess safety and efficacy

• Phase 3, a much larger number of patients receive drug to assess efficacy, safety monitoring continues

• Phase 4, after the drug is marketed, safety monitoring continues as all adverse effects are reported to the FDA.

- Identify changes that has occurred to the drug approval process as a result of the HIV/AIDS epidemic:

• Accelerated Development/Review: Allows the use of a surrogate marker (e.g., CD4+ cell counts) to predict clinical outcome (e.g., increased life span or decreased opportunistic infection)

• Treatment IND: Allow patients not in a clinical trial to receive drug prior to FDA approval provided the disease is life threatening and there are no available treatments.

• Parallel Track: Similar to Treatment IND, allows patients to receive drug prior to FDA approval – specific to HIV/AIDS.

-  Identify four processes by which lead compounds are discovered:

• Rational Approaches such as Structure-based design

• Screening

• Observation (e.g., serendipity)

• Existing drugs (e.g., to capitalize on a side-effect for the treatment of an un-related disorder)

HIV Drug Development Efforts

-  Know approximately how many drugs are currently in clinical trails for HIV/AIDS and associated diseases

• About 85, of which 33 are antivirals (not all of which target HIV) and 14 are vaccines.

HIV Life cycle

-  Be able to identify all the stages in the life cycle targeted by currently approved drugs

• Viral fusion with host cell

• Reverse Transcription

• Protease processing/virion maturation

-  Be able to describe the processes that occur during reverse transcription, including:

o  RNA-directed DNA synthesis

o  RNase H cleavage of the RNA

o  DNA-directed DNA synthesis

-  Be able to discuss the role of protease processing in the maturation of virions

• HIV protease required for the cleavage of large viral proteins into functional, smaller proteins such as reverse transcriptase, integrase, and protease

-  Be able to discuss the course of disease progression, from initial infection to AIDS, in terms of viral replication and the implication of this for drug treatment and resistance

Binding/Fusion Inhibitors

-  Be able to discuss the role of cellular proteins (co-receptors) in the binding and fusion of HIV virions:

• What evidence is there that co-receptors are required? (hCD4+ mouse cells can not be infected)

o  Describe a molecular biological experiment that identified a co-receptor

o  Know the differences between R5, X4, and dual tropic viruses.

o  Know the name of the only currently approved fusion inhibitor (Enfuvirtide/T-20)

Reverse Transcriptase Inhibitors

-  be able to distinguish between types of RT inhibitors:

o  Nucleoside analogs (NRTIs): Zidovudine (ZDV aka AZT), Didanosine (ddI), Zalcitabine (ddC), Stavudine (d4T), Lamivudine (3TC), Abacavir

o  Nucleotide analogs (NtRTIs): Tenofovir

o  Non-nucleoside analogs (NNRTIs): Nevirapine, Delaviridine, Efavirenz

-  Be able to identify the three parts of a nucleotide: base, sugar, phosphate; and two parts of a nucleoside: base and sugar

Protease inhibitors

-  Discuss the two factors which aided the discovery of HIV protease inhibitors:

• sequence similarity to rennin (involved in the hypertensive cascade)

• 3D structure of the enzyme

-  Be able to name the six approved protease inhibitors: Indinavir, Saquinavir, Ritonavir, Nelfinavir, Kaletra. Amprenavir

-  Be able to identify the three common problems with protease inhibitors:

• Pharmacokinetics

• Inhibition or extensive metabolism by metabolic enzymes

• Hyperlipidemia.

Vaccines

- Be able to distinguish vaccine goals:

• prevention vs. treatmen

- Be able to discuss vaccine strategies:

• Protein-based, vector-based, whole virus, DNA-based, prime and boost

- Be able to identify the following vaccines in clinical trials:

• REMUNE

• AIDSVAX

• ALVAC, Ad5

• EP HIV-1090

• AVX101