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Pleconaril
Pleconaril is an antiviral drug used against picornaviruses. Pleconaril is a capsid-function inhibitor, which blocks viral uncoating and attachment to host cell receptors in rhinoviruses and enteroviruses.

Mechanism of Action
Pleconaril is an oral medication taken at the start of a cold. The drug is most beneficial when given early. Human rhinoviruses (HRVs) contain four structural proteins labeled VP1-VP4. Proteins VP1,VP2 and VP3 are eight stranded anti-parallel β-barrel. VP4 is an extended poly-peptide chain on the viral capsid inner surface. Pleconaril binds to a hydrophobic pocket in the VP1 protein. Pleconaril has been shown in viral assesmbly to associate with viral particles. Through noncovalent, hydrophobic interactions compounds can bind to the hydrophobic pocket. Amino acids in positions 152 and 191 are a part of the VP1 drug binding pocket. Mutations in these amino acids decrease the efficiency of pleconaril. The resistant HRV have Phenylalanine at position 152 and Leucine at postion 191. Regular strains have Tyr152 and Val191.

In Coxsackievirus, Pleconaril efficiency correlates to the susceptibility of CVB3 with the amino acid at position 1092 in the hydrophobic pocket. Amino acid 1092 is in close to the central ring of capsid binders. The binding of pleconaril in the hydrophobic pocket creates conformational changes, which increases the rigidity of the virion and decreases the virions' ability to interact with its receptor. Drugs bind with the methylisoxazole ring close to the entrance pocket in VP1, the 3-fluromethyl oxadiazole ring at the end of the pocket and the phenyl ring in the center of the pocket.

Studies of Pleconaril
The results of two randomized, double blind, placebo studies found Pleconaril treatment could benefit patients suffering from colds due to picornaviruses. Participants in the studies were healthy adults from Canada and the United States, with self-diagnosed colds that had occurred within 24 hours of trail enrollment. Participants were randomly given a placebo or two 200 mg tablets to take three times daily for five days. To increase absorption it was recommended to be taken after a meal. To monitor the effectiveness of Pleconaril, participants recorded the severity of their symptoms and nasal mucosal samples were obtained at enrollment, day 3, day 6 and day 18. The two studies had a total of 2096 participates and more than 90% (1945) completed the trial. The most common reason for a participant not finishing the rial was an adverse event. Pleconaril treatment showed a reduction in nose blowing, sleep disturbance, and less cold medication used.

In vitro studies have shown resistance to pleconaril may emerge. The wild type resistance frequency to pleconaril was about 5X10^-5. Coxsackievirus B3(CVB3) strain Nancy and other mutants carry amino acid substitutions at position 1092 of Ile1092->Leu1092 or Ile1092->Met in VP1. The Ile->Leu mutation causes complete resistance to pleconaril. The study found resistance of CVB3 to pleconaril can be overcome by substitution of the central phenyl group. Methyl and Bromine substiutions created an increase of pleconaril activity towards sensitive and resistant strains. Amino acid substitutions in the hydrophobic pocket and receptor binding region of viral capsid proteins were shown to have an effect against the sensitivity of capsid binding antivirals.

Issues with Pleconaril
The U.S. Food and Drug Administration rejected pleconaril in 2002 due to the side effects. The most commonly reported side effects were mild to moderate headache, diarrhea, and nausea. Some women were having symptoms of spotting in between periods. Menstrual irregularities were reported by 3.5% of the 320 pleconaril treated women using oral contraceptives and by none of the 291 placebo treated women. In the clinical trial two women got pregnant due to the drug interfering with hormonal birth control. Other patients have described painful nasal inflammation. Another side effect of the Pleconaril drug trials was activation of cytochrome P-450 3A enzymes. In 2007, a pleconaril intransal spray had reached phase II clinical trail for the treatment of the common cold symptoms and asthma exacerbations. The results have yet to be reported.