Redesign Of An HIV-1 Entry Inhibitor Core Region Influences Its Kinetic and Pharmacokinetic Properties

Rama Karadsheh

doi:10.17918/00000920

The development of therapeutics for HIV-1 infection is necessary as drug-resistant viruses continue to emerge. The first and necessary step of infection is viral entry in which HIV-1 binds host cell receptors and fuses with the host cell membrane. This entry step is catalyzed by the envelope (Env) glycoprotein, which is an attractive yet underexploited therapeutic target in combination antiretroviral therapy (cART). A recent addition to the entry inhibitor class is Fostemsavir (brand name: Rukobia), which targets the gp120 subunit of Env and prevents viral attachment to the cell receptors. Fostemsavir is a pro-drug of BMS-626529/Temsavir that has addressed shortcomings of BMS-626529 with bioavailability and solubility. Prior to FDA approval of Fostemsavir, we explored bioisosteric replacement of BMS-626529 to identify novel lead compounds with enhanced solubility and pharmacokinetic properties. The piperazine core of BMS-626529 was replaced with other heterocyclic moieties to develop the SC series. Here, SC46 (azabicyclo[3.1.0]hexane core) and SC54 (dimethyl-piperazine core) were synthesized and assessed for antiviral activity and Env binding using surface plasmon resonance (SPR) kinetic analysis. These bioisosteres, in addition to previously published SC11, SC12, SC15, and SC28, were further characterized through in silico pharmacokinetic prediction analysis and metabolic stability assays. The SC bioisosteres displayed a range of potencies and retained their ability to interact with Env to different degrees. Replacement of the piperazine core to a flexible azetidine moiety in SC15 retained comparable binding affinity while replacement with a rigid azabicyclo[3.1.0]hexane moiety (SC28 and SC46) compromises the compounds affinity to a recombinant Env trimer, B41 SOSIP.664. Drug-likeness predictions in silico suggested that the bioisosteres were not more soluble than the parent BMS compound. It was also found that replacement of the piperazine core alters the stabilities of the compounds in human liver microsome assays. SC28 has more than twice the half-life than BMS-626529 and the lowest extraction ratio compared to the BMS compound and the other bioisosteres. We discovered that the orientation of SC28's core is critical for this increase in half-life. These analyses demonstrate that bioisosteric replacement is a rational method to create bioisosteres of a parent compound that retain biological activity but have altered kinetics and drug-like properties. Moreover, we have expanded our computational workflow to utilize in silico prediction of drug-like metrics and stability to further streamline lead hits in the discovery process of novel small-molecules that have anti-HIV-1 therapeutic potential.

Redesign Of An HIV-1 Entry Inhibitor Core Region Influences Its Kinetic and Pharmacokinetic Properties

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Redesign Of An HIV-1 Entry Inhibitor Core Region Influences Its Kinetic and Pharmacokinetic Properties

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