Case Study on Maraviroc, a CCR5 Antagonist for HIV Treatment

nName

nInstitution

nCourse

nDate

n

nOUTLINE

nIntroduction

nMaraviroc is a beneficial drug applied in the treatment of HIV

nIt possesses two major characteristics;

nLower affinity of HERG ion channel

nDesirable antiviral potency

nMaraviroc development Process

nThe entire process aims to develop of CCR5 antagonist molecules

nSteps:

nConnection of cyclobutane carboxamide through an alkyl piece to benzimidazole and tropane rings

nApproaches of modifying the lead Molecule (cyclobutane carboxamide);

nFirst approach encompassed altering the basicity of the tropane (central nitrogen)

nSecond approach involves replacement structure of the benzimidazole aromatic ring

nThird approach included determining of the benzimidazole molecule lipophilicity with the HERG ion

nFourth approach involved modification of the basicity of the cyclobutyl carboxamide via:

nfluorination of the molecule indicated both reduced HERG affinity and antiviral potency

nAfter fluorination and modification process, Maraviroc was produced which possessed a gemdifluorocyclohexyl group

nProduction of generic drugs such as Vicriviroc

nConclusion

nMaraviroc has outstanding antiviral action and display no substantial binding affinity of HERG

n

nSummary of the Article

nIntroduction

nMaraviroc drug is used for treatment of HIV whereby it targets the CCR5 receptor. The development of the drug used the fail fast fail cheap approach in order to minimize the undesirable side effects and improve affinity for CCR5. Precisely, the drug formulation process ensured that unwanted affinity of HERG was eliminated. The CCR5 receptor refers to a GPCR that is dynamically engaged in the HIV cycle and works as a co-receptor to gp120 and CD4 receptor prior to entry of the virus. Its antagonists are used actively to fight infection of HIV. Moreover, Human ether-a-go-go related gene (HERG) leads to problems such as unexpected cardiac death, and arrhythmia (Spencer, 2009).

nMaraviroc Development Process

nProcess involves formulation of CCR5 antagonist molecules. Researchers at Pfizer began with cyclobutane carboxamide connected through an alkyl piece to benzimidazole and tropane rings. However, this lead molecule demonstrated huge HERG channel affinity, hence analogues were developed aiming to eradicate such unwanted affinity whilst enhancing affinity of CCR5.

nVarious strategies were used to study the structure activity relationship by altering, first, the basicity of the tropane (central nitrogen). The main reason for this modification is to examine whether the alkalinity of the tropane nitrogen helped in improving CCR5 or HERG affinities. Structure 2 was produced comprising a bridgehead of oxygen. Moreover, the basicity of tropane was substantially minimized while there was similar affinity of the both compounds towards HERG ion (Spencer, 2009). This meant that the basicity of the tropane atom has minimal effect on the affinity of HERG.

nThe second approach involves replacement structure of the benzimidazole aromatic ring. Significantly, the elimination of fused benzimidazole aromatic ring produced a very effective antiviral action and which had low affinity of HERG. The decrease in affinity of HERG could be streamlined from molecular modelling tests in which benzimidine was placed into the binding area of a HERG model. The third approach involved the molecule lipophilicity (Lampe, 2013). The molecule implied that there was a decent intersection of the benzimidazole aromatic ring with a lipophilic area of the HERG ion. In this regard, eliminating the aromatic ring removed this interconnection and reduced affinity (Spencer, 2009).

nThe fourth approach involved modification of the basicity of the cyclobutyl carboxamide group, which is the lead compound. The molecular modelling tests indicated that there was a desirable hydrophobic association between the lead compound and HERG channel. The next process involved interruption of this interaction. Therefore, the ring size of cyclobutane carboxamide (4-structured) unit was changed to produce cyclopentane unit (5-structured) through homologation process. Consequently, the new molecule led to substantial rise in antiviral power and decrease of HERG affinity. The bigger cyclopentyl ring may have caused undesirable interconnection with the HERG ion binding sited leading to reduction in HERG affinity (Spencer, 2009). On the contrary, fluorination of the cyclobutane molecule indicated both reduced HERG affinity and antiviral potency.

nAfter fluorination process, the molecule was modified to produce Maraviroc, which possessed a gemdifluorocyclohexyl group. Notably, Maraviroc reserved outstanding antiviral action at the nanomolar stage, whilst demonstrating no substantial binding affinity of HERG. The absence of binding affinity of HERG was caused by big size of the cyclohexyl unit and the high polarization of the fluoro components (Spencer, 2009). Both features eliminated linking to a lipophilic area of the HERG ion channel. The next process involves generic production of CCR5 antagonists in order to enhance biological properties and overwhelmed possible virus resistance to the drug. For instance, Vicriviroc is a generic of Maraviroc and act as a CCR5 antagonist that prevents attachment of gp120 to the cell membrane hence eliminating HIV entry (Swenson, et al, 2011).

nConclusion

nCCR5 antagonists play an important part in the treatment of HIV. The drug contains beneficial structure that facilitates antiviral potency. Similarly, it has low affinity of HERG ion channel.

n

nReferences

nLampe, J. (2013). Case Studies in Modern Drug Discovery and Development.

nSpencer, J. (2009). Case study on Maraviroc, a CCR5 Antagonist for HIV treatment.

nSwenson, L. C., Mo, T., Dong, W. W., Zhong, X., Woods, C. K., Jensen, M. A., … & Heera, J. (2011). Deep sequencing to infer HIV-1 co-receptor usage: application to three clinical trials of maraviroc in treatment-experienced patients. Journal of Infectious Diseases, 203(2), 237-245.