Vicriviroc

Key takeaways

Vicriviroc belongs to chemistry; place it in that map before memorising details.
Learn the definition first, then one example that makes the definition concrete.
Connect Vicriviroc to a quantity you can measure, compute or draw — that is where exam questions come from.
Reproduce the core statement of Vicriviroc from memory before moving on to harder problems.

Reference excerpt

Vicriviroc, previously named SCH 417690 and SCH-D, is a pyrimidine CCR5 entry inhibitor of HIV-1. It was developed by the pharmaceutical company Schering-Plough. Merck decided to not pursue regulatory approval for use in treatment-experienced patients because the drug did not meet primary efficacy endpoints in late stage trials. Clinical trials continue in patients previously untreated for HIV.

HIV-1 background The mechanisms of a number of available anti-HIV drugs prevent either viral reverse transcriptase enzyme or protease enzyme, allowing the virus to enter the cell before these drugs take effect. However, CCR5 inhibitors such as vicriviroc, as well as other entry inhibitors of HIV-1, inhibit the initial stages of the virus life cycle.

HIV-1 entry HIV binds to and fuses with the target T-cells or macrophages with the help of gp120 and gp41, the only two proteins that are currently known to be exhibited on the surface of the viral envelope. One molecule of each protein associates noncovalently with the other on the viral membrane, and three of these units aggregate to form the gp120/gp41 heterotrimer, which traps the gp41 in a conformationally metastable state. Membrane fusion begins with the binding of gp120 to CD4, a glycoprotein which is expressed on the surface of the target cell. Upon binding, gp120 undergoes a conformational change, which causes the formation of the coreceptor binding site on gp120. All strains of HIV-1 use one of two coreceptors: CCR5 or CXCR4; coreceptor specificity will be described below. Once gp120 binds to the coreceptor, gp41 undergoes a conformational change that releases it from its once-metastable position. This change causes the hydrophobic N-terminus of the gp41 protein, also known as the fusion domain, to insert into the host cell membrane and anchor the virus into place. The insertion of gp41 into the target cell causes a subtle rearrangement in the gp41 protein that brings together two trimeric coiled coils, HR1 and HR2, to form a six-helix bundle. The bundle allows the viral and cellular membranes to approximate and eventually fuse together, leading to the release of the viral genome into the cytoplasm of the target cell.

Coreceptors and tropism The two coreceptors involved in the entry of HIV-1, CCR5 and CXCR4, belong to the larger family of 7-transmembrane segment (7TM) G-protein coupled receptors. HIV-1 can thus be classified according to specificity for one coreceptor or the other. R5 virus, also known as M-tropic HIV-1, targets macrophages and uses CCR5 as the coreceptor. X4 virus, or T-tropic HIV-1, targets T-cells and uses CXCR4 as the coreceptor. Dual-tropic strains of HIV-1, which utilize both receptors, also exist. Selectivity for one coreceptor or the other is especially dependent upon the V3 loop, a highly variable and structurally flexible region of gp120 that is composed of approximately 35 amino acids. Tropism can be predicted through the 11/25 method, which looks for basic amino acids at positions 11 and 25 in the V3 loop and suggests the presence of an X4 virus. Coreceptor usage, however, can change throughout the course of infection. 90% of patients in early phases of HIV-1 infection have R5 virus. However, after five years of infection, about 50% of all patients have detectable amounts of X4 virus. Causes for this switch are currently unclear. However, viral changes from CCR5 to CXCR4 coreceptor usage have been associated with a faster rate of CD4+ T-cell loss, rapid viral progression, and an increased rate of development of AIDS and death.

CCR5-Δ32 A focus on the CCR5 co-receptor as a potential target for anti-HIV medications began in 1996 with the discovery of CCR5-Δ32, or CCR5 delta-32, a mutational variant of the CCR5 coding gene. The deletion of 32 base pairs in this gene results in nonfunctional CCR5 receptors. While the frequency of this mutation within Caucasian populations is 0.0808, people of African or Asian descent do not appear to possess this allele. Δ32 homozygotes, or individuals who possess two copies of the Δ32 variant, have no functional CCR5 receptors and are consequently highly resistant to HIV infection. Individuals who inherit one copy of Δ32 variant and one copy of the normal CCR5 gene are CCR5 heterozygotes. Δ32 heterozygotes are still susceptible to HIV-1 infection, but the progression of the disease is significantly delayed compared to those with two normal copies of the CCR5 gene. CCR5 antagonists have been developed which cause deformation in the CCR5 co-receptor, leading to the cell's failure to bind with the HIV gp120 protein.

SCH-C and vicriviroc In 2001, Schering-Plough developed one of the first small molecule CCR5 antagonists, SCH-C or SCH 351125, which inhibited replication of a number of HIV-1 isolates that used CCR5 as a coreceptor for binding. However, SCH-C caused a modest but dose-dependent prolongation of the corrected cardiac QT interval (QTc), leading to examination of alternative compounds whose antiviral and pharmacokinetic properties exceeded those of first-generation compounds like SCH-C. Vicriviroc was discovered in high-throughput screening and structure-activity relationships (SAR) analysis. When compared with SCH-C, vicriviroc consistently and more actively inhibits viral replication, binds with higher affinity to CCR5 than SCH-C, and possesses a lower affinity for the human ether-a-go-go-related gene transcript ion channel, which may suggest a lower risk of cardiac effects.

… excerpt ends here. Continue reading the full article.

Illustrations

Worked examples

Example 1 — a first encounter with Vicriviroc

Start with the simplest possible case. Write down what Vicriviroc claims or describes in one sentence, then invent the smallest concrete situation in which that sentence is true. In chemistry, the smallest case is usually a single object, a single equation or a single measurement. Check that every symbol or term in your sentence has a meaning in that case.

Example 2 — changing one variable

Take the situation from Example 1 and change exactly one quantity: double it, halve it, or set it to zero. Predict what should happen to Vicriviroc before you calculate. Comparing your prediction with the result is the fastest way to find out whether you understand the idea or only the words.

Example 3 — an exam-style question

Typical questions about Vicriviroc ask you to (a) state it precisely, (b) apply it to given data, and (c) explain a limitation. Practise writing all three answers in under five minutes; the third part is what separates a full-mark answer from an average one.

Applications of Vicriviroc

In research: Vicriviroc appears in chemistry research whenever the underlying quantities have to be modelled precisely. Papers usually cite it as a starting assumption and then explore where it breaks down.
In technology and industry: Engineering practice reuses Vicriviroc in design rules, simulations and safety margins. Knowing the idea lets you read a specification sheet and understand why the numbers look the way they do.
In the classroom: Vicriviroc is common in secondary-school and first-year university syllabi. It links to neighbouring topics 4-(Trifluoromethyl)phenyl compounds, Carboxamides, Entry inhibitors, so understanding it makes those chapters shorter.
In everyday life: Look for Vicriviroc outside the textbook — in sport, cooking, traffic, electronics or the sky above you. An example you found yourself is remembered far longer than one you were given.

How to study Vicriviroc in 20 minutes

Read the reference excerpt below once, without taking notes.
Close the page and write down what Vicriviroc means in your own words.
Compare your version with the excerpt and mark what you missed.
Work through the three examples above with pen and paper.
Explain Vicriviroc out loud to somebody else — or to Teacher Smith in the lgStudy chat.

Frequently asked questions

What is Vicriviroc in simple terms?

Vicriviroc, previously named SCH 417690 and SCH-D, is a pyrimidine CCR5 entry inhibitor of HIV-1. It was developed by the pharmaceutical company Schering-Plough.

Why does Vicriviroc matter?

Because it connects several chemistry ideas at once: it gives you a definition you can apply, a quantity you can calculate, and a way to check whether a result is plausible.

How should I study Vicriviroc?

Read the excerpt, restate it from memory, then work through the examples and applications listed on this page. The five-step study plan above takes about twenty minutes.

What does this page cover?

It gives you a compact reference excerpt plus original lgStudy explanations, examples, applications and study material on Vicriviroc.